Compounds for the prevention and treatment of cardiovascular diseases

ABSTRACT

The present disclosure relates to compounds, which are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and their use for treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.

TECHNICAL FIELD

The present disclosure relates to compounds, which are useful forregulating the expression of apolipoprotein A-I (ApoA-I), and their use,for the treatment and prevention of cardiovascular disease and relateddisease states, including cholesterol- or lipid-related disorders, suchas, for example, atherosclerosis.

BACKGROUND

Epidemiologic data demonstrate an inverse relationship betweencirculating levels of high density lipoprotein cholesterol (HDL-C) andthe incidence of clinically significant atherosclerosis. Each 1 mg/dlincrement in the HDL-C serum level is associated with a 2-3% decrementin cardiovascular risk; a 1% reduction in LDL-C reduces coronary heartdisease (CHD) risk by 2% (Gordon et al. (1997) Am. J. Med. 62, 707-714).Experimental evidence further supports the protective effect of HDL-Cagainst cardiovascular disease. For example, in subjects with low HDL-C,administration of gemfibrozil results in a 6% increase in the HDL-Clevel and a corresponding 22% reduction of the CHD risk (Rubins et al.(1999) N. Engl. J. Med. 341, 410-418). Observations in genetic disordersassociated with low HDL-C due to reduced ApoA-I expression, alsoindicate the link between elevated risk of CHD and low HDL-C.

HDL-C appears to exert its anti-atherogenic effect by mediating reversecholesterol transport (RCT), in which cholesterol is recruited fromperipheral tissues and transported to the liver. In addition, HDL-C alsoexerts anti-inflammatory and anti-oxidant effects and promotesfibrinolysis. HDL-C particles protect against oxidation of LDL, animportant initial step in promoting cholesterol uptake by arterialmacrophages. HDL-C exists in two main forms, one containing bothapolipoprotein A-I (ApoA-I) and apolipoprotein A-II (ApoA-III), and theother containing ApoA-I without ApoA-II (Schultz et al. (1993) Nature365, 762-764). The cardioprotective effect of HDL-C is mostly, but notexclusively, attributable to ApoA-I.

Clinical and experimental data suggest that the production of ApoA-I isa critical determinant of circulating HDL-C. For example, persons withfamilial hyperalphalipoproteinemia (elevated ApoA-I) appear to beprotected from atherosclerosis, while those deficient in ApoA-I(hypoalphalipoproteinemia) show accelerated cardiovascular disease. Inaddition, various experimental manipulations to increase production ofApoA-I are associated with reduced atherogenicity. For example, humanApoA-I is protective in transgenic animal models (Shah et al. (1998)Circulation 97, 780-785; Rubin et al. (1991) Nature 353, 265-267), andtreatment with ApoA-I_(Milano) prevents atherosclerotic lesions andleads to regression of atherosclerotic plaques in human patients (Nissenet al. (2003) JAMA 290, 2292-2300). Further lines of researchdemonstrate that ApoA-I plays a role in enhancing reverse cholesteroltransport, attenuating oxidative stress, increasing paraoxonaseactivity, enhancing anticoagulant activity, and increasinganti-inflammatory activity (Andersson (1997) Curr. Opin. Lipidol. 8,225-228). Accordingly, ApoA-I is an attractive target for therapeuticintervention.

Currently available therapeutic agents that increase the plasmaconcentration of ApoA-I, for example, recombinant ApoA-I or peptidesthat mimic ApoA-I, have potential drawbacks with respect to, e.g.,stability during storage, delivery of active product, and in vivohalf-life. Thus, small molecule compounds that up-regulate theproduction of endogenous ApoA-I, such as, for example, up-regulators ofApoA-I expression, would be very attractive as new therapeutic agentsfor cardiovascular disease.

One class of compounds that are thought to contribute to the preventionof various diseases, including cancer and cardiovascular disease, ispolyphenols. Polyphenols are present in most food and beverages of plantorigin and are the most abundant dietary antioxidants (Scalbert &Williamson (2000) J. Nutr. 130, 2073S-2085S). However, the protectiveproperties of polyphenols have not been fully realized due to poorbioavailability (Manach et al. (2005) Am. J. Clin. Nutr. 81, 230S-242S),lack of clinical significance in various reported studies assessing them(Williamson & Manach (2005) Am. J. Clin. Nutr. 81, 243S-255S), anddeleterious effects at higher dose concentrations. For example, anabundant and available source of resveratrol, a well known stilbenepolyphenol, is red wine (Wu et. al. (2001) Int. J. Mol. Med. 8, 3-17).However, red wine cannot be consumed in therapeutically efficaciousquantities on a daily basis due to the numerous well documenteddeleterious effects of excessive alcohol consumption. The effects ofresveratrol may be better or safer in the absence of alcohol.

Several human clinical studies involving the anti-oxidant effect ofvarious polyphenols in various foods or beverages, have failed todemonstrate an unequivocal benefit with respect to primary clinicalendpoints, such as oxidative stress, lipemia, and inflammation(Williamson & Manach (2005) Am. J. Clin. Nutr. 81, 243S-255S). Forexample, out of twelve recent intervention studies with differingpolyphenol sources; six showed no effect on lipid parameters and sixshowed an improvement in the lipid parameters (Manach (2005) Curr. Opin.Lipidol. 16, 77-84). Such inconclusive data has limited the potentialuse of polyphenols, despite their many beneficial properties.

The use of naturally occurring polyphenols as potential therapeutics hasalso been impeded by the inability to achieve efficacious levels in thebody, partly due to poor bioavailability (Manach et al. (2005) Am. J.Clin. Nutr. 81, 230S-242S). The bioavailability of any given polyphenolvaries widely (from 1-26%) in different individuals. This variability isalso seen with administration of different polyphenols to the sameindividual due to differences in absorption, metabolism, and excretionrates. For example, polyphenol flavonoids, such as quercetin, have beenreported to have less than 1% intestinal absorption following oraladministration (Gugler et al. (1975) Eur. J. Clin. Pharm. 9, 229-234).In addition, some polyphenol metabolites are known to negativelyinfluence the biological activity of the parent compounds (Manach et al.(2005) Am. J. Clin. Nutr. 81, 230S-242S). Such metabolites often differfrom the parent compound in terms of toxicity, efficacy, and length ofresidence in the plasma. Another limiting factor is the poor solubilityof many polyphenols that limits the potential routes of administration.These and other factors have made it difficult to determine appropriatedosages of the naturally occurring polyphenols, naringenin orresveratrol, for use in humans.

Thus, there exists a need for polyphenol-like compounds to be developedas therapeutic agents for the treatment and prevention of cardiovasculardisease and related diseases, particularly, cholesterol- orlipid-related disorders, such as, for example, atherosclerosis. It istherefore one of the objects of the present invention to providecompounds that up-regulate the expression of ApoA-I. In addition, thecompounds may have more favorable pharmacological properties thannaturally occurring polyphenols.

SUMMARY

The present invention includes compounds that are useful for regulatingthe expression of apolipoprotein A-I (ApoA-I), and their use in thetreatment and prevention of cardiovascular disease and related diseasestates, including cholesterol- and lipid-related disorders, such as, forexample, atherosclerosis.

The methods of invention include administering to a mammal (e.g., ahuman) in need thereof a therapeutically effective amount of a compoundof Formula I:

wherein:

X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and NR₁₁,wherein R₁₁ may be the same or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and NR₁₂,wherein R₁₂ may be the same or different than R₁₄;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ areeach independently selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide,sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or

two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are connected in a 5 or 6-membered ringto form a bicyclic aryl or bicyclic heteroaryl;

each W is independently selected from C and N, wherein if W is N, then pis 0 and if W is C, then p is 1;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and adouble bond;

wherein if Y is O, then X is not CO;

wherein if X is O, then Z₁ is a single bond;

wherein if X is O and Z₂ is a single bond, then R₁₀ is not hydroxyl orester;

and pharmaceutically acceptable salts and hydrates thereof.

Also included are methods of administering alternative embodiments ofFormula I as set forth on pp. 27-68 and 107-139 of co-pending patentapplication Ser. No. 11/255,103 incorporated by reference herein.

The invention further includes compounds of Formula II and methods ofadministering a therapeutically effective amount of those compounds to amammal (e.g., a human) in need thereof:

wherein:

X is selected from CR₁₁, CR₁₁R₁₃, N and NR₁₁, wherein R₁₁ may be thesame or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CHOR₁₂, CS, S, SO, and SO₂,wherein R₁₂ may be the same or different than R₁₄;

R₁₁, R₁₂, R₁₃ and R₁₄ are each independently selected from hydrogen,unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl;

R₁ and R₃ are each independently selected from alkoxy, alkyl, alkenyl,alkynyl, amide, amino, halogen, hydroxyl, and hydrogen;

R₂ is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino,halogen, and hydrogen;

R₆ and R₈ are each independently selected from alkoxy, alkyl, alkenyl,alkynyl, amide, amino, halogen, hydrogen, heterocyclyl, and cycloalkyl;

R₅ and R₉ are each independently selected from alkyl, alkenyl, alkynyl,halogen, and hydrogen;

R₇ is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino,ether, hydrogen, and hydroxyl;

R₁₀ is selected from hydrogen and alkyl; or

two adjacent substituents selected from R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₉,R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are connected to form a group selected fromaryl, heteroaryl, cycloalkyl, and heterocyclyl;

wherein each of R₅ and R₉ may independently be taken together witheither R₁₀ or R₁₁ to form a group selected from aryl, heteroaryl,cycloalkyl, and heterocyclyl;

each W is independently selected from C and N, wherein if W is N, then pis 0 or 1, and if W is C, then p is 1 or 2;

wherein for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is0;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and adouble bond, wherein at least one of Z₁ or Z₂ must be a double bond;

and pharmaceutically acceptable salts and hydrates thereof.

In certain embodiments, the methods, compounds, and compositions of theinvention are useful for the prevention or treatment of diseases thatbenefit from raised ApoA-I or HDL, and diseases characterized by reducedApoA-I and/or HDL-C, abnormal lipid parameters, or lipid parametersindicative of high cholesterol. The methods, compounds, and compositionsof the invention can be used to increase expression of ApoA-I.Increasing expression of ApoA-I may refer to, but is not limited to,transcriptionally modulating the expression of the ApoA-I gene, therebyaffecting the level of the ApoA-I protein produced (synthesized andsecreted). An increase in ApoA-I levels may lead to an increase thelevels of HDL-C and/or increase in the functionality of HDL-C particles.Thus, the methods, compounds, and compounds of the invention may furtherbe used to reduce cholesterol levels. Accordingly, the methods,compounds, and compositions of the invention can be used for treatmentand prevention of cardiovascular disease and related disease states,particularly, cholesterol- or lipid-related disorders, such as, forexample, atherosclerosis.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts ApoA-I induction by2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(Example 20) in HepG2 Cells (48 h).

FIG. 2 depicts ApoA-I induction by2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(Example 20) in primary human hepatocytes (48 h).

FIG. 3 depicts plasma levels of ApoA-I in hApoA-I transgenic micereceiving2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(Example 20) (10, 30, and 60 mg/kg body weight) twice daily for 7 daysby oral gavage.

FIG. 4 depicts plasma levels of HDL cholesterol in hApoA-I transgenicmice receiving2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(Example 20) (10 and 30 mg/kg body weight) twice daily for 7 days byoral gavage.

FIG. 5 depicts plasma levels of ApoA-I in wild-type C57BL/6 micereceiving2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(Example 20) (10, 30 and 60 mg/kg of body weight) twice daily for 3 daysby intraperitoneal administration.

FIG. 6 depicts plasma levels of HDL cholesterol in wild-type C57BL/6mice receiving2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(Example 20) (10, 30 and 60 mg/kg of body weight) twice daily for 3 daysby intraperitoneal administration.

FIG. 7 depicts plasma levels of ApoA-I and tissue levels of ApoA-I mRNAin hApoA-I transgenic mice administered2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(Example 20) (30 mg/kg body weight) twice daily for 7 days by oralgavage.

DETAILED DESCRIPTION Definitions

The term “aldehyde” or “formyl” as used herein refers to —CHO.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms,referred to herein as (C₂-C₂₂)alkenyl, (C₂-C₈)alkenyl, and(C₂-C₆)alkenyl, respectively. Exemplary alkenyl groups include, but arenot limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl,pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl, etc.

The term “alkoxy” as used herein refers to an alkyl group attached to anoxygen (—O-alkyl-). “Alkoxy” groups also include an alkenyl groupattached to an oxygen (“alkenyloxy”) or an alkynyl group attached to anoxygen (“alkynyloxy”) groups. Exemplary alkoxy groups include, but arenot limited to, groups with an alkyl, alkenyl or alkynyl group of 1-22,1-8, or 1-6 carbon atoms, referred to herein as (C₁-C₂₂)alkoxy,(C₁-C₈)alkoxy, and (C₁-C₆)alkoxy, respectively. Exemplary alkoxy groupsinclude, but are not limited to methoxy, ethoxy, etc.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-22, 1-8,or 1-6 carbon atoms, referred to herein as (C₁-C₂₂)alkyl, (C₁-C₈)alkyl,and (C₁-C₆)alkyl, respectively. Exemplary alkyl groups include, but arenot limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, heptyl, octyl, etc.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms,referred to herein as (C₂-C₂₂)alkynyl, (C₂-C₈)alkynyl, and(C₂-C₆)alkynyl, respectively. Exemplary alkynyl groups include, but arenot limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl,methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and4-butyl-2-hexynyl, etc.

The term “amide” as used herein refers to the form —NR₉C(O)R_(b), or—C(O)NR_(b)R_(c), wherein R_(a), R_(b) and R_(c) are each independentlyselected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amide can beattached to another group through R_(b) or R_(c). The amide also may becyclic, for example R_(b) and R_(c) may be joined to form a 3- to12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-memberedring. The term “amide” encompasses groups such as sulfonamide, urea(ureido), carbamate, carbamic acid, and cyclic versions thereof. Theterm “amide” also encompasses an amide group attached to a carboxygroup, e.g., -amide-COOH or salts such as -amide-COONa, etc, an aminogroup attached to a carboxy group, e.g., -amino-COOH or salts such as-amino-COONa, etc.

The term “amine” or “amino” as used herein refers to the form—NR_(d)R_(e) or —N(R_(d))R_(e)— where R_(d) and R_(e) are independentlyselected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The aminocan be attached to the parent molecular group through the nitrogen. Theamino also may be cyclic, for example, R_(d) and R_(e) may be joinedtogether or with the N to form a 3- to 12-membered ring, e.g.,morpholino or piperidinyl. The term amino also includes thecorresponding quaternary ammonium salt of any amino group. Exemplaryamino groups include alkyl amino groups, wherein at least one of R_(d)and R_(e) is an alkyl group.

The term “aryl” as used herein refers to a mono-, bi-, or othermulti-carbocyclic, aromatic ring system. The aryl group can optionallybe fused to one or more rings selected from aryls, cycloalkyls, andheterocyclyls. The aryl groups of this invention can be substituted withgroups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide and thioketone. Exemplary aryl groups include, but are notlimited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl,and naphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but arenot limited to a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryl.”

The term “arylalkyl” as used herein refers to an alkyl group having atleast one aryl substituent, e.g. -aryl-alkyl-. Exemplary arylalkylgroups include, but are not limited to, arylalkyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylalkyl.”

The term “aryloxy” as used herein refers to an aryl group attached to anoxygen atom. Exemplary aryloxy groups include, but are not limited to,aryloxys having a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryloxy.”

The term “arylthio” as used herein refers to an aryl group attached toan sulfur atom. Exemplary arylthio groups include, but are not limitedto, arylthios having a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)arylthio.”

The term “arylsulfonyl” as used herein refers to an aryl group attachedto a sulfonyl group, e.g., —S(O)₂-aryl-. Exemplary arylsulfonyl groupsinclude, but are not limited to, arylsulfonyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylsulfonyl.”

The term “benzyl” as used herein refers to the group —CH₂-phenyl.

The term “bicyclic aryl” as used herein refers to an aryl group fused toanother aromatic or non-aromatic carbocylic or heterocyclic ring.Exemplary bicyclic aryl groups include, but are not limited to, naphthylor partly reduced forms thereof, such as di-, tetra-, orhexahydronaphthyl.

The term “bicyclic heteroaryl” as used herein refers to a heteroarylgroup fused to another aromatic or non-aromatic carbocylic orheterocyclic ring. Exemplary bicyclic heteroaryls include, but are notlimited to, 5,6 or 6,6-fused systems wherein one or both rings containheteroatoms. The term “bicyclic heteroaryl” also encompasses reduced orpartly reduced forms of fused aromatic system wherein one or both ringscontain ring heteroatoms. The ring system may contain up to threeheteroatoms, independently selected from oxygen, nitrogen, or sulfur.The bicyclic system may be optionally substituted with one or moregroups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide and thioketone. Exemplary bicyclic heteroaryls include, butare not limited to, quinazolinyl, benzothiophenyl, benzoxazolyl,benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl,isoquinolinyl, phthalazinyl, benzotriazolyl, benzopyridinyl, andbenzofuranyl.

The term “carbamate” as used herein refers to the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i)—, or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h) and R_(i) are each independently selected fromalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include,but are not limited to, arylcarbamates or heteroaryl carbamates, e.g.,wherein at least one of R_(g), R_(h) and R_(i) are independentlyselected from aryl or heteroaryl, such as pyridine, pyridazine,pyrimidine, and pyrazine.

The term “carbonyl” as used herein refers to —C(O)—.

The term “carboxy” as used herein refers to —COOH or its correspondingcarboxylate salts, e.g. —COONa, etc. The term carboxy also includes“carboxycarbonyl,” e.g., a carboxy group attached to a carbonyl group,e.g., —C(O)—COOH or salts such as —C(O)—COONa, etc.

The term “cyano” as used herein refers to —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to an oxygen.

The term “cycloalkyl” as used herein refers to a saturated orunsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of3-12 carbons, or 3-8 carbons, referred to herein as “(C₃-C₈)cycloalkyl,”derived from a cycloalkane. Exemplary cycloalkyl groups include, but arenot limited to, cyclohexanes, cyclohexenes, cyclopentanes, andcyclopentenes. Cycloalkyl groups may be substituted with alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Cycloalkyl groups can be fused to other cycloalkyl saturated orunsaturated, aryl, or heterocyclyl groups.

The term “dicarboxylic acid” as used herein refers to a group containingat least two carboxylic acid groups such as saturated and unsaturatedhydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylicacids include alkyl dicarboxylic acids. Dicarboxylic acids may besubstituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino,aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether,formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include,but are not limited to succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid,aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(−)-malicacid, (+)/(−) tartaric acid, isophthalic acid, and terephthalic acid.Dicarboxylic acids further include carboxylic acid derivatives thereof,such as anhydrides, imides, hydrazides, etc., for example, succinicanhydride, succinimide, etc.

The term “ester” refers to the structure —C(O)O—, —C(O)O—R_(j)—,—R_(k)C(O)O—R_(j)—, or —R_(k)C(O)O—, where O is not bound to hydrogen,and R_(j) and R_(k) can independently be selected from alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl,ether, haloalkyl, heteroaryl, heterocyclyl. R_(k) can be a hydrogen, butR_(j) cannot be hydrogen. The ester may be cyclic, for example thecarbon atom and R_(j), the oxygen atom and R_(k), or R_(j) and R_(k) maybe joined to form a 3- to 12-membered ring. Exemplary esters include,but are not limited to, alkyl esters wherein at least one of R_(j) orR_(k) is alkyl, such as —O—C(O)-alkyl-, —C(O)—O-alkyl-,-alkyl-C(O)—O-alkyl-, etc. Exemplary esters also include aryl orheteoraryl esters, e.g. wherein at least one of R_(j) or R_(k) is aheteroaryl group such as pyridine, pyridazine, pyrmidine and pyrazine,such as a nicotinate ester. Exemplary esters also include reverse estershaving the structure —R_(k)C(O)O—, where the oxygen is bound to theparent molecular group. Exemplary reverse esters include succinate,D-argininate, L-argininate, L-lysinate and D-lysinate. Esters alsoinclude carboxylic acid anhydrides and acid halides.

The term “ether” refers to the structure —R_(l)O—R_(m)—, where R_(l) andR_(m) can independently be alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, or ether. The ether can be attached to the parentmolecular group through R_(l) or R_(m). Exemplary ethers include, butare not limited to, alkoxyalkyl and alkoxyaryl groups. Ethers alsoincludes polyethers, e.g., where one or both of R_(l) and R_(m) areethers.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The term “haloalkyl” as used herein refers to an alkyl group substitutedwith one or more halogen atoms. “Haloalkyls” also encompass alkenyl oralkynyl groups substituted with one or more halogen atoms.

The term “heteroaryl” as used herein refers to a mono-, bi-, ormulti-cyclic, aromatic ring system containing one or more heteroatoms,for example one to three heteroatoms, such as nitrogen, oxygen, andsulfur. Heteroaryls can be substituted with one or more substituentsincluding alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl,arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl,halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro,phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide andthioketone. Heteroaryls can also be fused to non-aromatic rings.Illustrative examples of heteroaryl groups include, but are not limitedto, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl,pyrazolyl; imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl,pyrimidinyl, tetrazolyl, furyl, thienyl; isoxazolyl, thiazolyl, furyl,phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include,but are not limited to, a monocyclic aromatic ring, wherein the ringcomprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to hereinas “(C₂-C₅)heteroaryl.”

The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as usedherein refer to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-memberedring containing one, two, or three heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Heterocycles can be aromatic(heteroaryls) or non-aromatic. Heterocycles can be substituted with oneor more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone. Heterocycles also includebicyclic, tricyclic, and tetracyclic groups in which any of the aboveheterocyclic rings is fused to one or two rings independently selectedfrom aryls, cycloalkyls, and heterocycles. Exemplary heterocyclesinclude acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl,dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl,homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl,isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl,piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl,pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl,tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl,thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

The terms “hydroxy” and “hydroxyl” as used herein refers to —OH.

The term “hydroxyalkyl” as used herein refers to a hydroxy attached toan alkyl group.

The term “hydroxyaryl” as used herein refers to a hydroxy attached to anaryl group.

The term “ketone” as used herein refers to the structure—C(O)—R_(n)—(such as acetyl, —C(O)CH₃) or —R_(n)—C(O)—R_(o)—. The ketonecan be attached to another group through R_(n) or R_(o). R_(n) or R_(o)can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, orR_(n) or R_(o) can be joined to form a 3- to 12-membered ring.

The term “monoester” as used herein refers to an analogue of adicarboxylic acid wherein one of the carboxylic acids is functionalizedas an ester and the other carboxylic acid is a free carboxylic acid orsalt of a carboxylic acid. Examples of monoesters include, but are notlimited to, to monoesters of succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, oxalic acid and maleic acid.

The term “nitro” as used herein refers to the structure —NO₂.

The term “perfluoroalkoxy” as used herein refers to an alkoxy group inwhich all of the hydrogen atoms have been replaced by fluorine atoms.

The term “perfluoroalkyl” as used herein refers to an alkyl group inwhich all of the hydrogen atoms have been replaced by fluorine atoms.Exemplary perfluroalkyl groups include, but are not limited to, (C₁₋₅)perfluoroalkyl, such as trifluoromethyl, etc.

The term “perfluorocycloalkyl” as used herein refers to a cycloalkylgroup in which all of the hydrogen atoms have been-replaced by fluorineatoms.

The term “phenyl” as used herein refers to a 6-membered carbocyclicaromatic ring. The phenyl group can also be fused to a cyclohexane orcyclopentane ring. Phenyl can be substituted with one or moresubstituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide and thioketone.

The term “phosphate” as used herein refers to the structure —OP(O)O₂—,—R_(x)OP(O)O₂—, —OP(O)O₂R_(y)—, or —R_(x)OP(O)O₂R_(y)—, wherein R_(x)and R_(y) can be selected from alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclyl, and hydrogen.

The term “sulfide” as used herein refers to the structure —R_(z)S—,where R_(z) can be selected from alkyl, alkenyl, alkynyl, aryl,arylalkyl, cycloalkyl, haloalkyl, heteroaryl, and heterocyclyl. Thesulfide may be cyclic, forming a 3-12 membered ring. The term“alkylsulfide” as used herein refers to an alkyl group attached to asulfur atom.

The term “sulfinyl” as used herein refers to the structure —S(O)O—,—R_(p)S(O)O—, —R_(p)S(O)OR_(q)—, or —S(O)OR_(q)—, wherein R_(p) andR_(q) can be selected from alkyl, alkenyl, aryl, arylalkyl, cycloalkyl,haloalkyl, heteroaryl, heterocyclyl, and hydroxyl. Exemplary sulfinylgroups include, but are not limited to, alkylsulfinyls wherein at leastone of R_(p) or R_(q) is alkyl, alkenyl or alkynyl.

The term “sulfonamide” as used herein refers to the structure—(R_(r))—N—S(O)₂—R_(s)— or —R_(t)(R_(r))—N—S(O)₂—R_(s), where R_(t),R_(r), and R_(s) can be, for example, hydrogen, alkyl, alkenyl, alkynyl,aryl, cycloalkyl, and heterocyclyl. Exemplary sulfonamides includealkylsulfonamides (e.g., where R_(s) is alkyl), arylsulfonamides (e.g.,where R_(s) is aryl), cycloalkyl sulfonamides (e.g., where R_(s) iscycloalkyl), and heterocyclyl sulfonamides (e.g., where R_(s) isheterocyclyl), etc.

The term “sulfonate” as used herein refers to —OSO₃ ⁻. Sulfonateincludes salts such as —OSO₃Na, —OSO₃K, etc. and the acid —OSO₃H

The term “sulfonic acid” refers to —SO₃H— and its corresponding salts,e.g. —SO₃K—, —SO₃Na—.

The term “sulfonyl” as used herein refers to the structure R_(u)SO₂—,where R_(u) can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, andheterocyclyl, e.g., alkylsulfonyl. The term “alkylsulfonyl” as usedherein refers to an alkyl group attached to a sulfonyl group.“Alkylsulfonyl” groups can optionally contain alkenyl or alkynyl groups.

The term “thioketone” refers to the structure —R_(v)—C(S)—R_(w)—. Theketone can be attached to another group through R_(v) or R_(w). R_(v) orR_(w) can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl,or R_(v) and R_(w) can be joined to form a 3- to 12-membered ring.

“Alkyl,” “alkenyl,” “alkynyl,” “alkoxy,” “amino,” and “amide” groups canbe substituted with or interrupted by or branched with at least onegroup selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide, thioketone, ureido, and nitrogen. The substituents may bebranched to form a substituted or unsubstituted heterocycle orcycloalkyl.

As used herein, a “suitable substituent” refers to a group that does notnullify the synthetic or pharmaceutical utility of the compounds of theinvention or the intermediates useful for preparing them. Examples ofsuitable substituents include, but are not limited to: C₁₋₂₂, C₁₋₈, andC₁₋₆ alkyl, alkenyl or alkynyl; C₁₋₆ aryl, C₂-5 heteroaryl; C₃-7cycloalkyl; C₁₋₂₂, C₁₋₈, and C₁₋₆alkoxy; C₆ aryloxy; —CN; —OH; oxo;halo, carboxy; amino, such as —NH(C₁₋₂₂, C₁₋₈, or C₁₋₆ alkyl), —N(C₁₋₂₂,C₁₋₈, and C₁₋₆ alkyl)₂, —NH((C₆)aryl), or —N((C₆)aryl)₂; formyl;ketones, such as —CO(C₁₋₂₂, C₁₋₈, and C₁₋₆ alkyl), —CO((C₆ aryl) esters,such as —CO₂(C₁₋₂₂, C₁₋₈, and C₁₋₆ alkyl) and —CO₂ (C₆ aryl). One ofskill in art can readily choose a suitable substituent based on thestability and pharmacological and synthetic activity of the compound ofthe invention.

The term “pharmaceutically acceptable carrier” as used herein refers toany and all solvents, dispersion media, coatings, isotonic andabsorption delaying agents, and the like, that are compatible withpharmaceutical administration. The use of such media and agents forpharmaceutically active substances is well known in the art. Thecompositions may also contain other active compounds providingsupplemental, additional, or enhanced therapeutic functions.

The term “pharmaceutically acceptable composition” as used herein refersto a composition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present invention thatare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the compounds of the invention. Adiscussion is provided in Higuchi et al., “Pro-drugs as Novel DeliverySystems,” ACS Symposium Series, Vol. 14, and in Roche, E. B., ed.Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “pharmaceutically acceptable salt(s)” refers to salts of acidicor basic groups that may be present in compounds used in the presentcompositions. Compounds included in the present compositions that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form nontoxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfate, citrate, matate, acetate, oxalate, chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present compositions that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds included in the presentcompositions that are acidic in nature are capable of forming base saltswith various pharmacologically acceptable cations. Examples of suchsalts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium, andiron salts.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

Individual stereoisomers of compounds of the present invention can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers by wellknown methods, such as chiral-phase gas chromatography, chiral-phasehigh performance liquid chromatography, crystallizing the compound as achiral salt complex, or crystallizing the compound in a chiral solvent.Stereoisomers can also be obtained from stereomerically-pureintermediates, reagents, and catalysts by well known asymmetricsynthetic methods.

Geometric isomers can also exist in the compounds of the presentinvention. The present invention encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards. Unless otherwise specified, structures depicting doublebonds encompass both the E and Z isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ring,and the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

Embodiments of the Invention

One embodiment provides a method for increasing expression of ApoA-I ina mammal (e.g., a human) comprising administering a therapeuticallyeffective amount of a compound of Formula I:

wherein:

X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N, and NR₁₁,wherein R₁₁ may be the same or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N, and NR₁₂,wherein R₁₂ may be the same or different than R₁₄;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, and R₁₇ areeach independently selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide,sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or

two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are connected in a 5 or 6-membered ringto form a bicyclic aryl or bicyclic heteroaryl;

each W is independently selected from C and N, wherein if W is N, then pis 0 and if W is C, then p is 1;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and adouble bond;

wherein if Y is O, then X is not CO;

wherein if X is O, then Z₁ is a single bond;

wherein if X is O and Z₂ is a single bond, then R₁₀ is not hydroxyl orester;

and pharmaceutically acceptable salts and hydrates thereof.

Another embodiment provides a method for increasing expression ofApoA-II in a mammal (e.g., a human) comprising administering atherapeutically effective amount of a compound of Formula II:

wherein:

X is selected from CR₁₁, CR₁₁R₁₃, N and NR₁₁, wherein R₁₁ may be thesame or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CHOR₁₂, CS, S, SO, and SO₂,wherein R₁₂ may be the same or different than R₁₄;

R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selected from hydrogen,unsubstituted alkyl (preferably C₁₋₃ alkyl), unsubstituted alkenyl(preferably C₁₋₃ alkenyl), and unsubstituted alkynyl (preferably C₁₋₃alkynyl);

R₁ and R₃ are each independently selected from alkoxy (preferablymethoxy), alkyl, alkenyl, alkynyl, amide, amino, halogen (preferablychloride), hydroxyl, and hydrogen;

R₂ is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino,halogen (preferably bromide or chloride), and hydrogen;

R₆ and R₈ are each independently selected from alkoxy, alkyl (preferablymethyl), alkenyl, alkynyl, amide, amino, halogen (preferably chloride orfluoride), hydrogen, heterocyclyl, and cycloalkyl;

R₅ and R₉ are each independently selected from alkyl, alkenyl, alkynyl,halogen (preferably chloride), and hydrogen;

R₇ is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino,ether, ester, hydrogen, and hydroxyl;

R₁₀ is selected from hydrogen and alkyl (preferably methyl); or

two adjacent substituents selected from R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₉,R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are connected to form a group selected fromaryl, heteroaryl, cycloalkyl, and heterocyclyl;

wherein each of R₅ and R₉ may independently be taken together witheither R₁₀ or R₁₁ to form a group selected from aryl, heteroaryl,cycloalkyl, and heterocyclyl;

each W is independently selected from C and N, wherein if W is N, then pis 0 or 1, and if W is C, then p is 1;

wherein for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is0;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and adouble bond, wherein at least one of Z₁ or Z₂ is a double bond;

and pharmaceutically acceptable salts and hydrates thereof.

Another embodiment provides a method for increasing expression of ApoA-Iin a mammal (e.g., a human) comprising administering a therapeuticallyeffective amount of a compound of Formula II:

wherein:

X is selected from CH and N;

Y is selected from CO, CS, and SO₂;

R₁ and R₃ are each independently selected from alkoxy, alkyl, amino,halogen, and hydrogen;

R₂ is selected from alkoxy, alkyl, amino, and hydrogen;

R₆ and R₈ are each independently selected from alkoxy, amino, alkyl,hydrogen, and heterocyclyl;

R₅ and R₉ are each hydrogen;

R₇ is selected from alkoxy, alkyl, alkynyl, amide, amino, ether,hydrogen, and hydroxyl;

R₁₀ is hydrogen; or

two adjacent substituents selected from R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₉,and R₁₀ are connected to form group selected from aryl, heteroaryl,cycloalkyl and heterocyclyl;

wherein R₅ or R₉ may be taken together with R₁₀ to form a group selectedfrom aryl, heteroaryl, cycloalkyl, and heterocyclyl;

each W is independently selected from C and N, wherein if W is N, then pis 0 or 1, and if W is C, then p is 1;

wherein for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is0;

Z₁, Z₂, and Z₃ are each independently selected from a single bond and adouble bond, wherein at least one of Z₁ or Z₂ is a double bond;

and pharmaceutically acceptable salts and hydrates thereof.

The following is a list of specific exemplary embodiments that areencompassed by the invention:

1. A method for increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound ofFormula II:

wherein:

X is selected from CR₁₁, CR₁₁R₁₃, N, and NR₁₁, wherein R₁₁ may be thesame or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CHOR₁₂, CS, S, SO, and SO₂,wherein R₁₂ may be the same or different than R₁₄;

R₁₁, R₁₂, R₁₃ and R₁₄ are each independently selected from hydrogen,unsubstituted alkyl (preferably C₁₋₃ alkyl), unsubstituted alkenyl(preferably C₁₋₃ alkenyl), and unsubstituted alkynyl (preferably C₁₋₃alkynyl);

R₁ and R₃ are each independently selected from alkoxy (preferablymethoxy), alkyl, alkenyl, alkynyl, amide, amino, halogen (preferablychloride), hydroxyl, and hydrogen;

R₂ is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino,halogen (preferably chloride and fluoride), and hydrogen;

R₆ and R₈ are each independently selected from alkoxy, alkyl (preferablymethyl), alkenyl, alkynyl, amide, amino, halogen (preferably chloride),hydrogen, heterocyclyl, and cycloalkyl;

R₅ and R₉ are each independently selected from alkyl, alkenyl, alkynyl,halogen, and hydrogen;

R₇ is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino,ether, ester, hydrogen, and hydroxyl;

R₁₀ is selected from hydrogen and alkyl (preferably methyl); or

two adjacent substituents selected from R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₉,R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are connected to form a group selected fromaryl, heteroaryl, cycloalkyl, and heterocyclyl;

wherein each of R₅ and R₉ may independently be taken together with R₁₀or R₁₁ to form a group selected from aryl, heteroaryl, cycloalkyl, andheterocyclyl;

each W is independently selected from C and N, wherein if W is N, then pis 0 or 1, and if W is C, then p is 1;

wherein for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is0;

Z₁, Z₂, and Z₃ are each independently selected from a single bond and adouble bond, wherein at least one of Z₁ or Z₂ is a double bond;

and pharmaceutically acceptable salts and hydrates thereof.

In one embodiment, R₇ is not diethylamino or an alkoxy substituted witha carboxylate group.

In another embodiment, at least one of R₁₁, R₁₂, R₁₃, and R₁₄ is anunsubstituted (C₁₋₃) alkyl.

2. The method according to embodiment 1, wherein Z₁ is a double bond;

Z₂ and Z₃ are each a single bond;

X is selected from N and CR₁₁;

for W—(R₁₀)_(p), W is N and p is 1; and

Y is selected from CO, SO₂, SO, and CS.

3. The method according to embodiment 1, wherein Z₂ is a double bond;

X is NR₁₁;

for W—(R₁₀)_(p), W is N and p is 0; and

Y is selected from CO, SO₂, SO, and CS.

4. The method according to embodiment 1, wherein Z₁ and Z₃ are each adouble bond;

X is selected from N and CR₁₁;

for W—(R₁₀)_(p), W is N, and p is 0; and

Y is selected from CR₁₂, COR₁₂, and SO.

5. The method according to embodiment 1, wherein R₁ and R₃ are eachindependently an alkoxy.

6. The method according to embodiment 5, wherein R₆ and R₈ are eachindependently selected from alkyl and hydrogen; and

R₇ is selected from amino, hydroxyl, and alkoxy.

7. The method according to embodiment 6, wherein X is CR₁₁;

for W—(R₁₀)_(p), W is N and R₁₀ is hydrogen; and Y is CO.

8. The method according to embodiment 6, wherein X is N;

for W—(R₁₀)_(p), W is N and R₁₀ is hydrogen; and Y is CO.

9. The method according to embodiment 1, wherein R₅ and R₉ are eachhydrogen.

10. The method according to embodiment 1, wherein at least one of R₁,R₂, and R₃ is not hydrogen.

11. The method according to embodiment 10, wherein R₆ and R₈ are eachindependently selected from alkyl and hydrogen; and

R₇ is selected from amino, hydroxyl, and alkoxy.

12. The method according to embodiment 11, wherein X is CR₁₁;

for W—(R₁₀)_(p), W is N and R₁₀ is hydrogen; and Y is CO.

13. The method according to embodiment 11, wherein X is N;

for W—(R₁₀)_(p), W is N and R₁₀ is hydrogen; and Y is CO.

14. The method according to embodiment 1, wherein at least one of R₆,R₇, and R₈ is not hydrogen.

15. The method according to embodiment 14, wherein R₆ and R₈ are eachindependently selected from alkyl and hydrogen; and

R₇ is selected from amino, hydroxyl, and alkoxy.

16. The method according to embodiment 15, wherein X is CR₁₁;

for W—(R₁₀)_(p), W is N and R₁₀ is hydrogen; and Y is CO.

17. The method according to embodiment 16, wherein the compound ofFormula II is selected from:

-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 7); and-   7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one    (Example 16).

18. The method according to embodiment 15, wherein X is N;

for W—(R₁₀)_(p), W is N and R₁₀ is hydrogen; and Y is CO.

19. The method according to embodiment 18, wherein the compound ofFormula II is selected from:

-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 20);-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide    (Example 102);-   2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 98);-   2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 97);-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 46);-   2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 21); and-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one    (Example 51).

20. The method according to embodiment 1, wherein X is selected from CH,N, and NR₁₁, and Y is selected from CH, CO, and SO₂.

21. The method according to embodiment 20, wherein Z₁ is a double bond;

Z₂ and Z₃ are each a single bond; and

for W—(R₁₀)_(p), W is N and p is 1.

22. The method according to embodiment 20, wherein Z₂ is a double bond;

X is NR₁₁; and

for W—(R₁₀)_(p), W is N and p is 0.

23. The method according to embodiment 20, wherein Z₁ and Z₃ are each adouble bond;

X is selected from CH and N;

for W—(R₁₀)_(p), W is N and p is 0; and

Y is CH.

24. The method according to embodiment 1, wherein X is selected from CHand N, and Y is selected from CO and SO₂.

25. The method according to embodiment 24, wherein Z is a double bond,Z₂ and Z₃ are each a single bond, and for W—(R₁₀)_(p), W is N and R₁₀ ishydrogen.

26. The method according to embodiment 24, wherein Z₂ is a double bondand for W—(R₁₀)_(p), W is N and p is 0.

27. The method according to embodiment 1, wherein R₇ is an amino or analkoxy selected from the group represented by Formula III:

wherein:

-   -   A is selected from O and N;    -   n is selected from 0, 1, 2, 3, 4 and 5;    -   B is selected from —C(O)N(R_(h))₂—, —S(O)₂N(R_(h))₂—, —C(O)—,        —S(O)₂—, and —C(O)O—, wherein each R_(h) is independently        selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,        cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen;        and    -   R₂₀ is selected from C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl,        aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl,        heterocyclyl, and hydrogen.    -   In another embodiment, if A is O and B is —C(O)N(R_(h))₂—, then        R₂₀ is not an unsaturated cycloalkyl.

28. The method according to embodiment 27, wherein the compound ofFormula II is selected from:

-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl    cyclohexylcarbamate (Example 108);-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide    (Example 112);-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide    (Example 114);-   1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-phenylurea    (Example 117); and-   3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1,1-dimethylurea    (Example 118).

29. The method according to embodiment 1, wherein:

X is selected from CR₁₁, N, and NR₁₁,

Y is selected from CO, CS, and SO₂,

R₁₁ is selected from hydrogen, unsubstituted alkyl (preferably C₁₋₃alkyl), unsubstituted alkenyl (preferably C₁₋₃ alkenyl), andunsubstituted alkynyl (preferably C₁₋₃ alkynyl);

R₁ and R₃ are each independently selected from alkoxy (preferablymethoxy), alkyl, amino, halogen (preferably chloride), and hydrogen;

R₂ is selected from alkoxy, alkyl, alkenyl, amide, amino, halogen(preferably bromide or chloride), and hydrogen;

R₆ and R₈ are each independently selected from alkoxy, alkyl (preferablymethyl), amino, halogen (preferably chloride and fluoride), andhydrogen;

R₅ and R₉ are each independently selected from halogen (preferablychloride) and hydrogen;

R₇ is selected from alkoxy, alkyl, alkenyl, amide, amino, ether,hydrogen, and hydroxyl;

R₁₀ is selected from hydrogen and alkyl (preferably methyl); or

two adjacent substituents selected from R₁, R₂, R₃, R₆, R₇, R₈, R₁₀, andR₁₁ are connected to form a group selected from aryl, heteroaryl,cycloalkyl, and heterocyclyl;

each W is independently selected from C and N, wherein if W is N, then pis 0 or 1, and if W is C, then p is 1;

wherein for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is0;

Z₁, Z₂, and Z₃ are each independently selected from a single bond and adouble bond, wherein at least one of Z₁ or Z₂ is a double bond;

and pharmaceutically acceptable salts and hydrates thereof.

30. The method according to embodiment 29, wherein:

X is selected from N and CH;

Y is CO;

R₁ and R₃ are each independently selected from alkoxy and hydrogen;

R₂ is selected from alkoxy, alkyl, and hydrogen;

R₆ and R₈ are each independently selected from alkyl, alkoxy, chloride,and hydrogen;

R₅ and R₉ are each hydrogen;

R₇ is selected from amino, hydroxyl, alkoxy (preferably a substitutedethoxy group), and alkyl substituted with a heterocyclyl;

R₁₀ is hydrogen; or

two adjacent substituents selected from R₆, R₇, and R₈ are connected toform a heterocyclyl;

each W is independently selected from C and N, wherein if W is N, then pis 0 or 1, and if W is C, then p is 1;

for W—(R₁₀)_(p), W is N and p is 1;

for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is 0;

Z₁ is a double bond, and Z₂ and Z₃ are each a single bond;

with the proviso that at least one of R₁ and R₃ is alkoxy;

with the proviso that if R₇ is selected from hydroxyl and alkoxy, thenat least one of R₆ and R₈ are independently selected from alkyl, alkoxy,and chloride;

with the proviso that if R₇ is an amino, then X is N;

with the proviso that if for W—(R₇)_(p). W is N and p is 0, then atleast one of R₆ and R₈ is selected from alkyl, alkoxy, and chloride;

and pharmaceutically acceptable salts and hydrates thereof.

31. The method according to embodiment 30, wherein the compound ofFormula II is selected from:

-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 7);-   3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 9);-   3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one    (Example 11);-   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 13);-   3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 14);-   7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one    (Example 16);-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 20);-   3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 23);-   2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 31);-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 46);-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one    (Example 47);-   2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one    (Example 48);-   2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 67);-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one    (Example 70);-   2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 89);-   5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one    (Example 90);-   2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 91);-   N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide    (Example 99);-   2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 99); and-   4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide    (Example 101).

32. The method according to embodiment 1, wherein the compound ofFormula II is selected from:

-   3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one;-   4-Isoquinolin-3-yl-phenol;-   4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate    tetrahydrochloride;-   4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl    2-amino-5-guanidinopentanoate trihydrochloride;-   4-(1,6-naphthyridin-7-yl)phenol;-   3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methylisoquinolin-(2H)-one;-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;-   7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one;-   3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;-   3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;-   3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one;-   2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-naphthyridin-5(6H)-one;-   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;-   6,8-dimethoxy-3-(4-hydroxy-3,5-dimethylphenyl)-2H-1,2-benzothiazine-1,1-dioxide;-   7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one;-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholinomethyl)isoquinolin-1(2H)-one;-   4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol;-   3-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   4-(2-(4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)morpholine;-   3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;-   2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic    acid;-   5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one;-   5,7-dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one;-   2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one;-   2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one;-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;-   2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one;-   2-(4-(dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide;-   2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid;-   2-(4-(dimethylamino)pyridinon-1-yl)quinazolin-4(3H)-one;-   2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide;-   2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   2-(4-(dimethylamino)pyridinon-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one;-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one;-   2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one;-   7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-diethoxy-1,6-naphthyridin-5(6H)-one;-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one;-   2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;-   3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic    acid;-   N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;-   2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide;-   2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one-   5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one;-   N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide;-   7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;-   2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one;-   2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one;-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetic    acid;-   N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide;-   5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;-   2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   5,7-dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;-   7-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy-1,6-naphthyridin-5(6H)-one;-   2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol;-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one;-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;-   5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;-   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one;-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;-   2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one;-   5,7-dimethoxy-2-(6-methylpyridin-2-yl)quinazolin-4(3H)-one;-   5,7-dimethoxy-2-(6-(4-(methylthio)phenyl)pyridin-2-yl)quinazolin-4(3H)-one;-   2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;-   2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(1-phenyl-5-propyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one;-   2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   (E)-N′-(4-(5,7-dimeth    oxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide;-   6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;-   6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;-   6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;-   2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide;-   2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide;-   4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide;-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide;-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyphenoxy)acetic    acid;-   5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one;-   2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl    propylcarbamate;-   2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl    methylcarbamate;-   N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide;-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl    cyclohexylcarbamate;-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide;-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzenesulfonamide;-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide;-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide;-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzamide;-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide;-   1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-methylurea;-   1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-(4-methoxyphenyl)urea;-   1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-phenylurea;    and-   3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1,1-dimethylurea.

33. The method of embodiment 1, wherein the therapeutically effectiveamount of the compound of Formula II is administered with apharmaceutically acceptable carrier in a pharmaceutically acceptablecomposition.

34. The method of embodiment 1, further comprising treating orpreventing a cardiovascular diseases, or cholesterol- or lipid-relateddisorder.

35. A compound of Formula II:

wherein:

X is selected from N and CR₁₁;

Y is selected from CO and SO₂;

R₁₁ is selected from hydrogen, unsubstituted alkyl (preferably C₁₋₃alkyl), unsubstituted alkenyl (preferably C₁₋₃ alkenyl), andunsubstituted alkynyl (preferably C₁₋₃ alkynyl);

R₁ and R₃ are each independently selected from alkoxy (preferablymethoxy), alkyl, amino, halogen (preferably chloride), and hydrogen;

R₂ is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino,halogen (preferably bromide or chloride), and hydrogen;

R₆ and R₈ are each independently selected from alkyl (preferablymethyl), alkoxy, amino, halogen (preferably chloride or fluoride), andhydrogen;

R₅ and R₉ are each hydrogen;

R₇ is selected from amino, amide, alkyl, hydroxyl, and alkoxy;

R₁₀ is selected from hydrogen and methyl;

each W is independently selected from C and N, wherein if W is N, then pis 0 or 1, and if W is C, then p is 1;

for W—(R₁₀)_(p), W is N and p is 1;

for W—(R₇)_(p), W is C and p is 1;

for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is 0;

Z₁ is a double bond, and Z₂ and Z₃ are each a single bond;

with the proviso that if R₁ is hydrogen, then R₃ is alkoxy;

with the proviso that if R₃ is hydrogen, then R₁ is selected from aminoand alkoxy;

with the proviso that if R₇ is selected from alkyl, hydroxyl, andalkoxy, then at least one of R₆ and R₈ is independently selected fromalkyl, alkoxy, amino, and halogen;

with the proviso that if R₇ is amino, then X is N;

and pharmaceutically acceptable salts and hydrates thereof.

36. The compound according to embodiment 35, wherein X is N; forW—(R₁₀)_(p), W is N and R₁₀ is hydrogen; and R₇ is amino.

37. The compound according to embodiment 36, wherein the compound ofFormula II is2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(Example 46).

38. The compound according to embodiment 35, wherein for W—(R₁₀)_(p), Wis N and R₁₀ is hydrogen; and R₇ is selected from hydroxyl and alkoxy.

39. The compound according to embodiment 38, wherein the compound ofFormula II is selected from:

-   7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one    (Example 15);-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide    (Example 102);-   2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 98);-   2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 97);-   2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 20); and-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one    (Example 51).

40. The compound according to embodiment 38, wherein R₆ and R₈ are eachindependently alkyl;

R₂ is hydrogen; and

R₇ is selected from hydroxyl and alkoxy (preferably substituted with ahydroxyl.)

41. The compound according to embodiment 40, wherein the compound ofFormula II is selected from:

-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 7); and-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 19).

42. The compound according to embodiment 35, wherein R₇ is selected froman amino or an alkoxy selected from the group represented by FormulaIII:

wherein:

-   -   A is selected from O and N;    -   n is selected from 0, 1, 2, 3, 4 and 5;    -   B is selected from —C(O)N(R_(h))₂—, —S(O)₂N(R_(h))₂—, —C(O)—,        —S(O)₂—, —C(O)O—, wherein each R_(h) is selected from alkyl,        alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,        heteroaryl, heterocyclyl, and hydrogen; and    -   R₂₀ is selected from (C₁-C₆) alkyl, (C₁-C₆) alkenyl, (C₁-C₆)        alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl,        heterocyclyl, and hydrogen.

In another embodiment, if A is O and B is —C(O)NH—, then R₂₀ is not anunsaturated cycloalkyl.

43. The compound according to embodiment 42, wherein the compound ofFormula II is selected from:

-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl    cyclohexylcarbamate (Example 108);-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide    (Example 112);-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide    (Example 114);-   1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-phenylurea    (Example 117); and-   3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1,1-dimethylurea    (Example 118).

44. The compound according to embodiment 35, wherein the compound ofFormula II is selected from:

-   3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 10);-   7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one    (Example 16);-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one    (Example 17);-   2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 21);-   2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 28);-   2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 31);-   2-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 32);-   5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one    (Example 43);-   7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one    (Example 50);-   2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one    (Example 52);-   2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide    (Example 55);-   2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 56);-   2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 57);-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one    (Example 58);-   N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide    (Example 60);-   7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one    (Example 61);-   2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one    (Example 63);-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetic    acid (Example 64);-   N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide    (Example 65);-   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one    (Example 68);-   5,7-dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one    (Example 69);-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 72);-   2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 75);-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-pyrido[2,3-d]pyrimidin-4(3H)one    (Example 78);-   5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one    (Example 79);-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one    (Example 84);-   (E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide    (Example 93);-   2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 96);-   2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 99);-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyphenoxy)acetic    acid (Example 103);-   2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl    propylcarbamate (Example 105);-   2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl    methylcarbamate (Example 106);-   N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide    (Example 107);-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide    (Example 109);-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzenesulfonamide    (Example 110);-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide    (Example 111);-   N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzamide    (Example 113);-   1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-methylurea    (Example 115); and-   1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-(4-methoxyphenyl)urea    (Example 116).

45. A compound selected from:

-   3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one (Example 1);-   4-Isoquinolin-3-yl-phenol (Example 2);-   4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate    tetrahydrochloride (Example 3);-   4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl    2-amino-5-guanidinopentanoate trihydrochloride (Example 4);-   4-(1,6-naphthyridin-7-yl)phenol (Example 5);-   7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (Example    8);-   2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-naphthyridin-5(6H)-one    (Example 12);-   4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (Example 18);-   4-(2-(4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)morpholine    (Example 22);-   2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one    (Example 34);-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one    (Example 35);-   2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one (Example    36);-   2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid (Example    39);-   2-(4-(dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one (Example    40);-   2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide (Example    41);-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one (Example    45);-   7-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy-1,6-naphthyridin-5(6H)-one    (Example 74);-   2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol    (Example 76);-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one    (Example 77);-   5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one    (Example 80);-   6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one    (Example 94);-   6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one    (Example 95);-   6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one    (Example 95);-   5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one (Example 26);-   5,7-dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (Example 27);-   2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example    29);-   5,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one (Example 33);-   2-(4-(dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 37);-   2-(4-(dimethylamino)pyridin-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one    (Example 44);-   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H)-one    (Example 71);-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one    (Example 82);-   2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 83);-   5,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one (Example 85);-   5,7-dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one    (Example 86);-   5,7-dimethoxy-2-(6-methylpyridin-2-yl)quinazolin-4(3H)-one (Example    87);-   5,7-dimethoxy-2-(6-(4-(methylthio)phenyl)pyridin-2-yl)quinazolin-4(3H)-one    (Example 88);-   2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example    92); and-   5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one    (Example 104).

46. A pharmaceutical composition comprising a compound according toembodiment 35 and a pharmaceutically acceptable carrier.

47. A method of treating cardiovascular disease, or cholesterol- orlipid-related disorders comprising administering a therapeuticallyeffective amount of a compound according to embodiment 35.

48. A method of increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound accordingto embodiment 35.

49. A compound of Formula II:

wherein:

X is selected from N and CH;

Y is CO;

R₁ and R₃ are each independently selected from alkoxy and hydrogen;

R₂ is selected from alkoxy, alkyl, and hydrogen;

R₆ and R₈ are each independently selected from alkyl, alkoxy, halogen(preferably chloride), and hydrogen;

R₅ and R₉ are each hydrogen;

R₇ is selected from amino, hydroxyl, alkoxy (preferably a substitutedethoxy group), and alkyl substituted with a heterocyclyl;

R₁₀ is hydrogen; or

two adjacent substituents selected from R₆, R₇, and R₈ are connected toform a heterocyclyl;

each W is independently selected from C and N, wherein if W is N, then pis 0 or 1, and if W is C, then p is 1;

for W—(R₁₀)_(p), W is N and p is 1;

for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is 0;

Z₁ is a double bond, and Z₂ and Z₃ are each a single bond;

with the proviso that if R₂ is alkoxy or hydrogen, then least one of R₁and R₃ is alkoxy;

with the proviso that if R₇ is selected from hydroxyl and alkoxy, thenat least one of R₆ and R₈ are independently selected from alkyl, alkoxy,and chloride;

with the proviso that if R₇ is an amino, then X is N;

with the proviso that if for W—(R₇)_(p), W is N and p is 0, then atleast one of R₆ and R₈ is selected from alkyl, alkoxy, and chloride;

and pharmaceutically acceptable salts and hydrates thereof.

50. The compound according to embodiment 49, wherein the compound ofFormula II is selected from:

-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 7);-   3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 9);-   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 13);-   3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 14);-   7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one    (Example 16);-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 20);-   3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one    (Example 23);-   2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 31);-   2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 42);-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 46);-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one    (Example 47);-   2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one    (Example 48);-   2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 67);-   2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one    (Example 70);-   2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 89);-   5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one    (Example 90);-   2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 91);-   N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide    (Example 99);-   2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 99);-   and    4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide    (Example 101).

51. The compound according to embodiment 49, wherein R₇ is selected froman amino or an alkoxy selected from the group represented by FormulaIII:

wherein:

-   -   A is selected from O and N;    -   n is selected from 0, 1, 2, 3, 4 and 5;    -   B is selected from —C(O)N(R_(h))₂—, —S(O)₂N(R_(h))₂—, —C(O)—,        —S(O)₂—, and —C(O)O—, wherein each R_(h) is independently        selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,        cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen;        and    -   R₂₀ is selected from (C₁-C₆) alkyl, (C₁-C₆) alkenyl, (C₁-C₆)        alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl,        heterocyclyl, and hydrogen.

In another embodiment, if A is O and B is —C(O)NH—, then R₂₀ is not anunsaturated cycloalkyl.

52. The compound of embodiment 51, wherein the compound of Formula II isselected from:

-   N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide    (Example 99);-   2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 99); and-   4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide    (Example 101).

53. A pharmaceutical composition comprising a compound according toembodiment 49 and a pharmaceutically acceptable carrier.

54. A method of treating cardiovascular disease, or cholesterol- orlipid-related disorders comprising administering a therapeuticallyeffective amount of a compound according to embodiment 49.

55. A method of increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound accordingto embodiment 49.

56. A compound of Formula II:

wherein:

X is selected from N and CR₁₁;

Y is selected from CO and SO₂;

R₁₁ is selected from hydrogen, unsubstituted alkyl, unsubstitutedalkenyl, and unsubstituted alkynyl;

R₁ and R₃ are each independently selected from alkoxy (preferablymethoxy), alkyl, amino, halogen (preferably chloride) and hydrogen;

R₂ is selected from —N—C(O)—R₁₈, —N—SO₂—R₁₈, —CH₂—C(R₁₈)₃, —CH₂—N(R₁₈)₂,and —CH₂—O—R₁₈, wherein each R₁₈ is independently selected from alkoxy,alkyl, alkenyl, amide, amino, aryl, arylalkyl, cycloalkyl, haloalkyl,halogen, heteroaryl, heterocyclyl, and hydrogen;

R₆ and R₈ are each independently selected from alkyl (preferablymethyl), alkoxy, amino, halogen (preferably chloride or fluoride), andhydrogen;

R₅ and R₉ are each hydrogen;

R₇ is selected from amino, amide, alkyl, hydroxyl, and alkoxy;

R₁₀ is selected from hydrogen and methyl;

each W is independently selected from C and N, wherein if W is N, then pis 0 or 1, and if W is C, then p is 1;

for W—(R₁₀)_(p), W is N and p is 1;

for W—(R₇)_(p), W is C and p is 1;

for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is 0;

Z₁ is a double bond, and Z₂ and Z₃ are each a single bond;

with the proviso that if R₇ is selected from alkyl, hydroxyl, andalkoxy, then at least one of R₆ and R₈ is independently selected fromalkyl, alkoxy, amino, and halogen;

and pharmaceutically acceptable salts and hydrates thereof.

57. The compound according to embodiment 56, wherein X is N;

for W—(R₁₀)_(p), W is N, and p is 1; and R₁₀ is hydrogen.

58. The compound according to embodiment 57, wherein the compound ofFormula II is selected from:

-   N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide    (Example 54);-   2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one    (Example 62);-   N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide    (Example 73); and-   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morphoinomethyl)quinazolin-4(3H)-one    (Example 81).

59. The compound according to embodiment 56, wherein X is CH; forW—(R₁₀)_(p), W is N and R₁₀ is hydrogen; and R₇ is selected fromhydroxyl and alkoxy.

60. The compound according to embodiment 59, wherein the compound ofFormula II is selected from:

-   3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one    (Example 11);-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholinomethyl)isoquinolin-1(2H)-one    (Example 17); and-   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one    (Example 51).

61. The compound according to embodiment 56, wherein R₆ and R₈ are eachindependently alkyl; and R₇ is selected from hydroxyl and alkoxy(preferably substituted with a hydroxyl).

62. The compound according to embodiment 56, wherein R₇ is selected froman amino or an alkoxy selected from the group represented by FormulaIII:

wherein:

-   -   A is selected from O and N;    -   n is selected from 0, 1, 2, 3, 4 and 5;    -   B is selected from —C(O)N(R_(h))₂—, —S(O)₂N(R_(h))₂—, —C(O)—,        —S(O)₂—, —C(O)O—, wherein each R_(h) is selected from alkyl,        alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,        heteroaryl, heterocyclyl, and hydrogen; and    -   R₂₀ is selected from (C₁-C₆) alkyl, (C₁-C₆) alkenyl, (C₁-C₆)        alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl,        heterocyclyl, and hydrogen.

In another embodiment, if A is O and B is —C(O)NH—, then R₂₀ is not anunsaturated cycloalkyl.

63. The compound according to embodiment 56, wherein R₆ and R₈ are eachindependently alkyl.

64. A pharmaceutical composition comprising a compound according toembodiment 56 and a pharmaceutically acceptable carrier.

65. A method of treating cardiovascular disease, or cholesterol- orlipid-related disorders comprising administering a therapeuticallyeffective amount of a compound according to embodiment 56.

66. A method of increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound accordingto embodiment 56.

67. A compound of Formula II:

wherein:

X is selected from N and CR₁₁;

Y is selected from CO and SO₂;

R₁₁ is selected from hydrogen, unsubstituted alkyl, unsubstitutedalkenyl, and unsubstituted alkynyl;

R₁ is selected from alkoxy (preferably methoxy) or amino;

R₃ is alkoxy (preferably methoxy);

R₂ is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino,halogen (preferably bromide or chloride), and hydrogen;

R₆ and R₈ are each independently selected from alkyl, alkoxy, amino,halogen (preferably chloride or fluoride), and hydrogen;

R₅ and R₉ are each hydrogen;

R₇ is selected from amino, amide, alkyl, hydroxyl, and alkoxy;

R₁₀ is selected from hydrogen and methyl;

each W is independently selected from C and N, wherein if W is N, then pis 0 or 1, and if W is C, then p is 1;

for W—(R₁₀)_(p), W is N and p is 1;

for W—(R₇)_(p), W is C and p is 1;

for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is 0;

Z₁ is a double bond, and Z₂ and Z₃ are each a single bond;

with the proviso that if R₇ is hydroxyl, then X is N;

and pharmaceutically acceptable salts and hydrates thereof.

68. The compound according to embodiment 67, wherein X is selected fromN and CH;

R₁₀ is hydrogen; and

R₇ is selected from hydroxyl and alkoxy.

69. The compound according to embodiment 68, wherein the compound ofFormula II is selected from:

-   2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 24);-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic    acid (Example 25);-   5,7-dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one (Example 30);    and-   2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide    (Example 38).

70. The compound according to embodiment 67, wherein X is selected fromN and CH;

R₁₀ is hydrogen; and

R₇ is selected from amide and amino.

71. The compound according to embodiment 70, wherein the compound ofFormula II is selected from:

-   5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one    (Example 43);-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 46);-   5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one (Example    49);-   N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide    (Example 65); and-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-pyrido[2,3-d]pyrimidin-4(3H)one    (Example 78).

72. The compound according to embodiment 67, wherein X is selected fromN and CH;

R₁₀ is hydrogen; and

R₇ is alkyl.

73. The compound according to embodiment 72, wherein the compound ofFormula II is selected from:

-   3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic    acid (Example 53);-   5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one    (Example 59);-   5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one    (Example 66); and-   2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one    (Example 67).

74. The compound according to embodiment 67, wherein R₆ and R₈ are eachindependently alkyl.

75. The compound according to embodiment 67, wherein R₇ is selected froman amino or an alkoxy selected from the group represented by FormulaIII:

wherein:

-   -   A is selected from O and N;    -   n is selected from 0, 1, 2, 3, 4 and 5;    -   B is selected from —C(O)N(R_(h))₂—, —S(O)₂N(R_(h))₂—, —C(O)—,        —S(O)₂—, —C(O)O—, wherein each R_(h) is selected from alkyl,        alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,        heteroaryl, heterocyclyl, and hydrogen; and    -   R₂₀ is selected from (C₁-C₆) alkyl, (C₁-C₆) alkenyl, (C₁-C₆)        alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl,        heterocyclyl, and hydrogen.

In another embodiment, if A is O and B is —C(O)NH—, then R₂₀ is not anunsaturated cycloalkyl.

76. The compound according to embodiment 75, wherein R₆ and R₈ are eachindependently alkyl.

77. A pharmaceutical composition comprising a compound according toembodiment 67 and a pharmaceutically acceptable carrier.

78. A method of treating cardiovascular disease, or cholesterol- orlipid-related disorders comprising administering a therapeuticallyeffective amount of a compound according to embodiment 67.

79. A method of increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound accordingto embodiment 67.

Pharmaceutical Formulations and Methods of Treatment

The present disclosure also provides pharmaceutical compositionscomprising compounds as disclosed herein, formulated together with oneor more pharmaceutically acceptable carriers. These formulations includethose suitable for oral, rectal, topical, buccal and parenteral (e.g.subcutaneous, intramuscular, intradermal, or intravenous)administration, although the most suitable form of administration in anygiven case will depend on the degree and severity of the condition beingtreated and on the nature of the particular compound being used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of the compound as powder or granules;as a solution or a suspension in an aqueous or non-aqueous liquid; or asan oil-in-water or water-in-oil emulsion. As indicated, suchformulations may be prepared by any suitable method of pharmacy whichincludes the step of bringing into association the active compound andthe carrier or excipient (which may constitute one or more accessoryingredients). The carrier must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and must not bedeleterious to the recipient. The carrier may be a solid or a liquid, orboth, and may be formulated with the compound as a unit-doseformulation, for example, a tablet, which may contain from about 0.05%to about 95% by weight of the active compound. Other pharmacologicallyactive substances may also be present including other compounds. Theformulations of the invention may be prepared by any of the well knowntechniques of pharmacy consisting essentially of admixing thecomponents.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmacologicallyadministrable compositions can, for example, be prepared by dissolving,dispersing, etc., an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. In general, suitable formulations may beprepared by uniformly and intimately admixing the active compound with aliquid or finely divided solid carrier, or both, and then, if necessary,shaping the product. For example, a tablet may be prepared bycompressing or molding a powder or granules of the compound, optionallywith one or more accessory ingredients. Compressed tablets may beprepared by compressing, in a suitable machine, the compound in afree-flowing form, such as a powder or granules optionally mixed with abinder, lubricant, inert diluent and/or surface active/dispersingagent(s). Molded tablets may be made by molding, in a suitable machine,the powdered compound moistened with an inert liquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising a compound in a flavored base, usually sucrose andacacia or tragacanth, and pastilles comprising the compound in an inertbase such as gelatin and glycerin or sucrose and acacia.

Formulations of the present invention suitable for parenteraladministration comprise sterile aqueous preparations of the compounds,which are approximately isotonic with the blood of the intendedrecipient. These preparations are administered intravenously, althoughadministration may also be effected by means of subcutaneous,intramuscular, or intradermal injection. Such preparations mayconveniently be prepared by admixing the compound with water andrendering the resulting solution sterile and isotonic with the blood.Injectable compositions according to the invention may contain fromabout 0.1 to about 5% w/w of the active compound.

Formulations suitable for rectal administration are presented asunit-dose suppositories. These may be prepared by admixing the compoundwith one or more conventional solid carriers, for example, cocoa butter,and then shaping the resulting mixture.

Formulations suitable for topical application to the skin may take theform of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.Carriers and excipients which may be used include Vaseline, lanoline,polyethylene glycols, alcohols, and combinations of two or more thereof.The active compound is generally present at a concentration of fromabout 0.1% to about 15% w/w of the composition, for example, from about0.5% to about 2%.

The amount of active compound administered may be dependent on thesubject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician. Forexample, a dosing schedule may involve the daily or semi-dailyadministration of the encapsulated compound at a perceived dosage ofabout 1 μg to about 1000 mg. In another embodiment, intermittentadministration, such as on a monthly or yearly basis, of a dose of theencapsulated compound may be employed. Encapsulation facilitates accessto the site of action and allows the administration of the activeingredients simultaneously, in theory producing a synergistic effect. Inaccordance with standard dosing regimens, physicians will readilydetermine optimum dosages and will be able to readily modifyadministration to achieve such dosages.

A therapeutically effective amount of a compound or compositiondisclosed herein can be measured by the therapeutic effectiveness of thecompound. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being used. In one embodiment, thetherapeutically effective amount of a disclosed compound is sufficientto establish a maximal plasma concentration. Preliminary doses as, forexample, determined according to animal tests, and the scaling ofdosages for human administration is performed according to art-acceptedpractices.

Toxicity and therapeutic efficacy can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferable.

Data obtained from the cell culture assays or animal studies can be usedin formulating a range of dosage for use in humans. Therapeuticallyeffective dosages achieved in one animal model may be converted for usein another animal, including humans, using conversion factors known inthe art (see, e.g., Freireich et al., Cancer Chemother. Reports50(4):219-244 (1966) and Table 1 for Equivalent Surface Area DosageFactors).

TABLE 1 To: Mouse Rat Monkey Dog Human From: (20 g) (150 g) (3.5 kg) (8kg) (60 kg) Mouse 1 ½ ¼ ⅙ 1/12 Rat 2 1 ½ ¼ 1/7 Monkey 4 2 1 ⅗ ⅓ Dog 6 4⅗ 1 ½ Human 12 7 3 2 1

The therapeutically effective dosage (i.e. ED₅₀) may vary with thedosage form, route of administration, the subject's age, condition, andsex, as well as the severity of the medical condition in the subject.The dosage may be determined by a physician and adjusted, as necessary,to suit observed effects of the treatment.

In one embodiment, a compound as disclosed herein, or a pharmaceuticallyacceptable salt or hydrate thereof, is administered in combination withanother therapeutic agent. The other therapeutic agent can provideadditive or synergistic value relative to the administration of acompound of the present invention alone. The therapeutic agent can be,for example, a statin; a PPAR agonist, e.g., a thiazolidinedione orfibrate; a niacin, a RVX, FXR or LXR agonist; a bile-acid reuptakeinhibitor; a cholesterol absorption inhibitor; a cholesterol synthesisinhibitor; an ion-exchange resin; an antioxidant; an inhibitor ofAcylCoA cholesterol acyltransferase (ACAT inhibitor); a tyrophostine; asulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; anapolipoprotein E regulator; a HMG-CoA reductase inhibitor, a microsomaltriglyceride transfer protein; an LDL-lowing drug; an HDL-raising drug;an HDL enhancer; a regulator of the apolipoprotein A-IV and/orapolipoprotein genes; or any cardiovascular drug.

In one embodiment, a method of treating or preventing cardiovasculardisease, cholesterol- or lipid-related disorders, comprisesadministering to a mammal (e.g., human) a therapeutically effectiveamount of a disclosed compound. The disclosed compound may beadministered as a pharmaceutically acceptable composition, comprising adisclosed compound and a pharmaceutically acceptable carrier.

As used herein, the term “cardiovascular disease” refers to diseases anddisorders of the heart and circulatory system. Exemplary cardiovasculardiseases, including cholesterol- or lipid-related disorders, include,but are not limited to acute coronary syndrome, angina,arteriosclerosis, atherosclerosis, carotid atherosclerosis,cerebrovascular disease, cerebral infarction, congestive heart failure,congenital heart disease, coronary heart disease, coronary arterydisease, coronary plaque stabilization, dyslipidemias,dyslipoproteinemias, endothelium dysfunctions, familialhypercholeasterolemia, familial combined hyperlipidemia,hypoalphalipoproteinemia, hypertriglyceridemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, cardiac ischemia, metabolicsyndrome, multi-infarct dementia, myocardial infarction, obesity,peripheral vascular disease, reperfusion injury, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, and lipoprotein abnormalitiesassociated with Alzheimer's disease, obesity, diabetes mellitus,syndrome X, impotence, multiple sclerosis, Parkinson's diseases andinflammatory diseases.

One embodiment provides methods for altering lipid metabolism in apatient, e.g., increasing the ratio of HDL to LDL or ApoA-I to ApoB inthe blood of a patient, comprising administering to the patient acomposition of the invention in an amount effective to alter lipidmetabolism.

One embodiment provides methods for elevating the levels of ApoA-Iassociated molecules, such as HDL, in the blood of a mammal, comprisingadministering to the mammal a composition comprising a disclosedcompound or composition in an amount effective to elevate levels ofApoA-I and HDL associated proteins in the mammal.

In one embodiment, “treatment” or “treating” refers to an ameliorationof a disease or disorder, or at least one discernible symptom thereof.In another embodiment, “treatment” or “treating” refers to anamelioration of at least one measurable physical parameter, notnecessarily discernible by the patient. In another embodiment,“treatment” or “treating” refers to inhibiting the progression of adisease or disorder, either physically, e.g., stabilization of adiscernible symptom, physiologically, e.g., stabilization of a physicalparameter, or both. In yet another embodiment, “treatment” or “treating”refers to delaying the onset of a disease or disorder. For example,treating a cholesterol disorder may comprise decreasing bloodcholesterol levels.

One embodiment provides a compound for administration to a patient, suchas a human, as a preventative measure against cardiovascular diseases,including-cholesterol- or lipid-related disorders. As used herein,“prevention” or “preventing” refers to a reduction of the risk ofacquiring a given disease or disorder. An additional aspect of theinvention provides a method for prevention of arteriosclerosis lesiondevelopment in a mammal, including the development of newarteriosclerotic lesions. In another aspect, the present inventionprovides a method for regressing arteriosclerosis lesions.

In another embodiment, the present compositions are administered as apreventative measure to a patient, such as a human having a geneticpredisposition to a cardiovascular disease, including cholesterol- orlipid-related disorders, for example familial hypercholeasterolemia,familial combined hyperlipidemia, atherosclerosis, a dyslipidemia, adyslipoproteinemia, or Alzheimer's disease.

In another embodiment, the compositions of the invention areadministered as a preventative measure to a patient having a non-geneticpredisposition to a cardiovascular disease, including cholesterol- orlipid-related disorders. Examples of such non-genetic predispositionsinclude, but are not limited to, cardiac bypass surgery and percutaneoustransluminal coronary angioplasty, which often leads to restenosis, anaccelerated form of atherosclerosis; diabetes in women, which oftenleads to polycystic ovarian disease; and cardiovascular disease, whichoften leads to impotence.

Angioplasty and open heart surgery, such as coronary bypass surgery, maybe required to treat cardiovascular diseases, such as atherosclerosis.These surgical procedures entail using invasive surgical devices and/orimplants, and are associated with a high risk of restenosis andthrombosis. Accordingly, the compounds of the invention may be used ascoatings on surgical devices (e.g., catheters) and implants (e.g.,stents) to reduce the risk of restenosis and thrombosis associated withinvasive procedures used in the treatment of cardiovascular diseases.

In another embodiment, the present compositions may be used for theprevention of one disease or disorder and concurrently treating another(e.g., prevention of polycystic ovarian disease while treating diabetes;prevention of impotence while treating a cardiovascular disease).

Diseases and conditions associated with “diabetes mellitus” as definedherein refer to chronic metabolic disorder(s) caused by absolute orrelative insulin deficiency including, but not limited to hyperglycemia,hyperinsulinemia, hyperlipidemia, insulin resistance, impaired glucosemetabolism, obesity, diabetic retinopathy, macular degeneration,cataracts, diabetic nephropathy, glomerulosclerosis, diabeticneuropathy, erectile dysfunction, premenstrual syndrome, vascularrestenosis, ulcerative colitis, skin and connective tissue disorders,foot ulcerations, metabolic acidosis, arthritis, osteoporosis andimpaired glucose tolerance.

Preparation of Compounds

Exemplary compounds of the invention represented by the general formulaA:

wherein:R_(a) may be selected from groups including, but not limited to, alkoxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,cycloalkyl, ether, halogen, haloalkyl, heteroaryl, heterocyclyl,hydrogen and hydroxyl; R_(b) may be selected from groups including, butnot limited to, alkyl and hydrogen; X may be selected from, e.g.,CR_(c), N and NR_(c), where R_(c) represents substituents such as alkyl,alkenyl, alkynyl, and hydrogen; Y may be selected from, e.g., CR_(c),CO, CS, and SO₂ where R_(c) is as defined above; and Z₃ may be a singleor double bond; may be synthesized from readily available startingmaterials as outlined in the exemplary schemes below. It should beappreciated that these designations are non-limiting examples.

Reaction of aldehyde 1 with alkyne 2 in the presence of a Pd(II)catalyst, such as dichlorobis(triphenylphosphine)-palladium(II),followed by treatment with t-butylamine and Cul, can afford isoquinoline3 as shown in Scheme 1.

Scheme 2 illustrates that condensation followed by oxidation of amide 4and aldehyde 5 can provide quinazolinone 6. Condensation can occur undera variety of conditions, such as NaHSO₃ and p-TsOH in dimethylacetamide,I₂ in the presence of K₂CO₃, and treatment with catalytictrifluoroacetic acid followed by DDQ oxidation. Conversion ofquinazolinone 6 into quinazoline 7 can be achieved by treatment withPOCl₃, followed by dehydration in the presence of a palladium catalyst.

Condensation of amide 8 with nitrile 9 in the presence of n-BuLi canafford isoquinolinone 10, as shown in Scheme 3.

Scheme 4 provides a method for synthesizing benzothiazine-1,1-dioxide13. Amide coupling of sulfonamide 11 with carboxylic acid 12 can befollowed by treatment with n-BuLi to afford 13.

Abbreviations used herein denote the following compounds, reagents andsubstituents: acetic acid (AcOH); 2,2′-azobisisobutyronitrile (AIBN);N-bromosuccinimide (NBS); N-tert-butoxycarbonyl (Boc);t-butyldimethylsilyl (TBDMS); m-chloroperoxybenzoic acid (mCPBA);dimethylaminopyridine (DMAP); dichloromethane (DCM); dimethylformamide(DMF); dimethylsulfoxide (DMSO); ethanol (EtOH); ethyl acetate (EtOAc);1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl);1-hydroxybenzotriazole (HOBt); iodomethane (MeI); lithiumhexamethyldisilazide (LHMDS); methanol (MeOH); methoxymethyl (MOM);tetrahydrofuran (THF); triethylamine (Et₃N); lithium aluminum hydride(LAH); p-toluenesulfonic acid (p-TSA); tetrabutylammonium fluoride(TBAF); N-methyl morpholine (NMM); N,N-dimethylacetamide (DMA); twicedaily (BID), once daily (QD).

Example 1

3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one

To a solution of n-methyl-o-toluamide (2.0 g, 13.4 mmol) in THF (30 mL),n-butyl lithium (12.3 mL, 30.8 mmol, 2.5 M solution in hexane) was addedslowly under nitrogen with cooling (ice-salt bath), maintaining thetemperature below 20° C. After completion of addition, the mixture wasstirred for 1 h at 0° C., then cooled to −50° C. and a solution of4-methoxy benzonitrile (2.14 g, 16.08 mmol) in THF (5 mL) was addedquickly. The cooling bath was removed and the solution was allowed towarm to room temperature. Saturated aqueous NH₄Cl solution was addedwith cooling and the solid was isolated by filtration to give themethoxy compound (2.2 g, 65%). The methoxy compound (750 mg, 2.98 mmol)was added to a 50 mL flask and pyridinium hydrochloride (10 g) wasadded. The mixture was heated at 190° C. for 2 h, then cooled to roomtemperature, diluted with water, neutralized with NaHCO₃, and the solidwas isolated by filtration to give3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (600 mg, 84%). Selected data:MS (ES) m/z: 238.92, 237.89; MP 239-241° C.

Example 2

4-Isoquinolin-3-yl-phenol

To a solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) and4-methoxyphenyl acetylene (1.58 g, 12 mmol) in 40 mL of triethylaminewere added dichlorobis(triphenylphosphine)palladium(II) (140 mg, 2 mol%) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture washeated at 50° C. under nitrogen for 3 h. The reaction mixture was cooledto room temperature and the ammonium salt was removed by filtration. Thefiltrate was concentrated under reduced pressure. Purification of thecrude compound by column chromatography (silica gel 230-400 mesh; 10%ethyl acetate in hexanes as eluent) afforded 2-(4-methoxyphenylethynyl)benzaldehyde (2.1 g, 89%). The above compound (2.06 g,8.73 mmol) and t-butylamine (3.83 g, 52.4 mmol) were stirred undernitrogen for 24 h at room temperature. The resulting mixture wasextracted with ether and the organic layer was dried over anhydrousNa₂SO₄, and concentrated to give the imine (2.4 g, 94%), which was usedin the next step without further purification. To a solution of theabove imine (2.39 g, 8.2 mmol) in 100 mL anhydrous DMF was added (0.156g, 0.82 mmol) copper (I) iodide, and the solution was flushed withnitrogen. The reaction mixture was heated at 100° C. for 4 h. Themixture was cooled to room temperature, and diluted with ether (200 mL).The organic layer was washed with saturated aqueous ammonium chloride(3×100 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated to give the crude compound as a dark colored solid.Purification by column chromatography (silica gel 230-400 mesh; 10%ethylacetate in hexanes as eluent) afforded3-(4-methoxyphenyl)isoquinoline (1.064 g, 55%), as a white solid. The3-(4-methoxyphenyl)isoquinoline (1.05 g, 4.47 mmol) was suspended in 30mL hydroiodic acid and 12 mL of acetic acid was added. The reactionmixture was stirred at 110° C. for 2 h, then cooled to room temperature.The precipitate formed was filtered off, washed with acetic acid (2×5mL) and dried under vacuum, to give a yellow solid. The crude compoundwas purified by triturating with 5% methanol in ether to give4-isoquinolin-3-yl-phenol (0.83 g, 84%) as a white powder. Selecteddata: MS (ES) m/z: 222.89, 221.86; MP 218-219° C.

Example 3

4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoatetetrahydrochloride

To a solution of 4-isoquinolin-3-yl-phenol (0.133 g, 0.6 mmol) inanhydrous DMF (5 mL) were added HOBt (0.081 g, 0.6 mmol),Boc-Arg-(Boc)₂-OH (0.285 g, 0.6 mmol), and EDCl (0.115 g, 0.6 mmol).N,N-Diisopropyl ethyl amine (0.233 g, 1.8 mmol) was added and themixture was stirred at room temperature for 24 h. Water (15 mL) wasadded and the white precipitate was filtered off, washed with water anddried under vacuum to give 0.3 g (74%) of the Boc-arginine derivative.The above compound (0.3 g) was dissolved in anhydrous dichloromethane(10 mL). HCl gas was bubbled into the solution at 0° C. for 4 h. Ayellow precipitate was formed. The solvent was removed and the resultingsolid was dried under vacuum. Triturating with ether gave4-(isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoatetetrahydrochloride (0.2 g, 86%). Selected data: MS (ES) m/z: 222.96(M+1-Arg), 221.99 (M-Arg); MP 198-201° C.

Example 4

4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl2-amino-5-guanidinopentanoate trihydrochloride

A mixture of 3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (150 mg, 0.63mmol) in DMF (5 mL), diisopropyl ethyl amine (245 mg, 1.89 mmol), EDCl(133 mg, 0.696 mmol), Boc-Arg (330 mg, 0.696 mmol) and HOBt (94 mg,0.696 mmol) was stirred at room temperature for 24 h under nitrogen. Thereaction mixture was diluted with water and the solid was collected byfiltration. The crude product was purified by column chromatographyusing 5% MeOH in CH₂Cl₂, to give the tri-Boc ester product (375 mg 85%).HCl gas was bubbled through a solution of the tri-Boc ester (325 mg,0.468 mmol) in CH₂Cl₂ (10 mL) for 6 h at 0° C. The solid was filteredoff and washed with CH₂Cl₂ to give4-(1-oxo-1,2-dihydroisoquinolin-3-yl)phenyl2-amino-5-guanidinopentanoate trihydrochloride (170 mg, 72%). Selecteddata: MS (ES) m/z: 237.25 (M-Arg); ¹³C-NMR (DMSO-d₆): δ 168.8, 163.4,157.7, 151.0, 139.8, 139.5, 133.4, 132.8, 128.9, 127.4, 127.3, 127.25,125.6, 122.6, 104.2, 55.6, 52.5, 27.7, 25.0.

Example 5

4-(1,6-naphthyridin-7-yl)phenol

To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL)were added dichlorobis(triphenylphosphine)palladium (11) (140 mg, 2 mol%) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture washeated at 50° C. under nitrogen for 3 h, then cooled to roomtemperature. The ammonium salt was removed by filtration. The filtratewas concentrated under reduced pressure leaving 2-(4-methoxyphenylethynyl)pyridine-3-carboxaldehyde (2.35 g, 99%) as a yellow solid.2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol)and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24h at room temperature. The resulting mixture was extracted with etherand dried over anhydrous Na₂SO₄. Removal of solvent gave the expectedimine (2.72 g, 97%), which was used in next step without furtherpurification. To a solution of the above imine (2.7 g, 9.23 mmol) inanhydrous DMF (50 mL) was added copper (I) iodide (0.190 g, 0.1 mmol).The reaction mixture was heated at 100° C. for 4 h, then cooled to roomtemperature and diluted with ether (200 mL). The organic layer waswashed with a saturated aqueous ammonium chloride solution (3×100 mL).The organic layer was dried over anhydrous Na₂SO₄. Removal of solventgave the crude compound as a dark-colored solid. Purification by columnchromatography (silica gel 230-400 mesh; 30% ethyl acetate in hexanes aseluent) afforded 7-(4-methoxy phenyl) [1,6]naphthridine (0.730 g, 33%)as a brown solid. To a solution of 7-(4-methoxy phenyl)[1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrousN-methyl-2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol)and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture wasstirred at 190° C. for 1 h under nitrogen. The reaction mixture wascooled to room temperature. The compound was purified by columnchromatography to give 4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) asa pale yellow solid. Selected data: MS (ES) m/z: 223.95, 222.95; MP219-221° C.

Example 6

3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one

To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.3mmol) in CH₂Cl₂ (30 mL), oxalyl chloride (3.62 g, 28.5 mmol) was addedand the mixture was stirred at room temperature for 16 h. The solventand excess oxalyl chloride were removed at reduced pressure. The solidwas dissolved in CH₂Cl₂ (10 mL) and methyl amine hydrochloride (1.33 g,42.81 mmol) was added on cooling and the mixture was stirred at roomtemperature for 4 h. The solvent was removed and the crude product waspurified by chromatography using 5% methanol in CH₂Cl₂, to give 1.3 g ofthe amide intermediate (43% yield). To a solution of the amideintermediate (1.29 g, 6.16 mmol) in THF (30 mL), n-butyl lithium (5.6mL, 14.18 mmol, 2.5 M solution in hexane) was added slowly undernitrogen with cooling (ice-salt bath), maintaining the temperature below20° C. The mixture was stirred for 1 h at 0° C., then cooled to −50° C.and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10mL) was added quickly. The cooling bath was removed and the mixture wasstirred at room temperature for 16 h. Saturated aqueous NH₄Cl solutionwas added with cooling, and the layers were separated. The organic layerwas washed with water, brine, dried over Na₂SO₄ and concentrated to givethe crude intermediate, which was purified by chromatography using 5%methanol in CH₂Cl₂, to give two products (1) 678 mg of isoquinoline in26% yield and (2) 780 mg of quinalone product in 27% yield. To asuspension of the above quinalone product (780 mg, 1.65 mmol) in ethanol(20 mL), conc. HCl (2 mL) was added and the mixture was heated at 70° C.for 2 h. The reaction mixture was cooled to room temperature and thesolvent was removed and purified by chromatography to give3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (215 mg, 44%).Selected data: MS (ES) m/z: 297.93; MP 245-247° C.

Example 7

3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methylisoquinolin-1(2H)-one(left) And3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one(right)

To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.61 g, 13.1mmol) in CH₂Cl₂ (50 mL), oxalyl chloride (3.38 g, 26.6 mmol) was addedand the mixture was stirred at room temperature for 16 h. The solventand excess oxalyl chloride were removed at reduced pressure. The solidwas dissolved in CH₂Cl₂ (10 mL) and methyl amine (1.24 g, 39.9 mmol)with cooling and was stirred at room temperature for 4 h. The solventwas removed and crude product was purified by chromatography by using 5%methanol in CH₂Cl₂ to give the amide (2.27 g, 82%). To a solution of theabove amide (2.27 g, 10.9 mmol) in THF (50 mL), n-butyl lithium (9.98mL, 25.0 mmol, 2.5 M solution in hexane) was added slowly under nitrogenwith cooling, maintaining the temperature below 20° C. The mixture wasstirred for 1 h at 0° C., then cooled to −50° C., and a solution of4-O-TBDMS-3,5-dimethyl benzonitrile (2.97 g, 11.39 mmol) in THF (10 mL)was added quickly, the cooling bath was removed and the mixture wasstirred for 16 h at room temperature. A saturated aqueous NH₄Cl solutionwas added with cooling, and the layers were separated. The organic layerwas washed with water, brine, dried over Na₂SO₄ and concentrated to give3.9 g of the crude product mixture. A suspension of the crude productmixture (3.9 g) in ethanol (20 mL) was heated with conc. HCl (2 mL) at80° C. for 2 h. The reaction mixture was cooled to room temperature andthe solvent was removed. The solid was dissolved in water andneutralized by NaHCO₃, followed by extraction with CH₂Cl₂. The productwas purified by chromatography to give two products:3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methylisoquinolin-1(2H)-one(128 mg, 5%) and3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (340mg, 9%). Selected data for3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methylisoquinolin-1(2H)-one:MS (ES) m/z: 340.01 (M); MP 253-254° C. Selected data for3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one: MS(ES) m/z: 326.00; MP 226-227° C.

Example 8

7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one

Oxalyl chloride (1.90 mL, 21.8 mmol) was added to 2-methyl nicotinicacid (1.50 g, 10.9 mmol) in anhydrous dichloromethane (20 mL) withtriethylamine (1.6 mL, 11.5 mmol) and the reaction mixture was kept atroom temperature overnight before the solvent was removed. THF was addedto the residue and ammonia gas was bubbled through for 2 h. The THF wasremoved and the residue was dissolved into methanol and water and the pHwas adjusted to 10.0 with potassium carbonate. The mixture wasconcentrated. After column chromatography the desired amide was isolated(1.10 g, 73.8%).

NaH (0.428 g, 10.7 mmol, 60% in mineral oil) was added to4-hydroxy-3,5-dimethylbenzonitrile (1.50 g, 10 mmol) in anhydrous DMF (8mL). Benzyl bromide (1.83 g, 10.7 mmol) was added and the reaction waskept at room temperature overnight. The reaction mixture was poured intowater. The isolated solid was further washed with hexane to yield thedesired ether building block (2.0 g, 84.3%). It was used in the nextreaction without further purification. The above amide (0.65 g, 4.77mmol) in anhydrous THF (15 mL) was added drop-wise to BuLi (7.5 mL, 1.60M) at −20° C. The reaction mixture was kept at this temperature for 1 hand then the above ether building block (1.13 g, 4.77 mmol) in THF (20mL) was added drop-wise at −20° C. and the reaction was stirred for 1.5h. The reaction temperature was increased to room temperature andcontinued for a further 1 h. Water (20 mL) was added and the mixture wasstirred for a while before the solvent was removed and the residue waspurified by column chromatography to yield the desired intermediate(0.50 g, 29.4%). A 50 mL flask was charged with the above describedintermediate (0.50 g, 0.0014 mol) and pyridine hydrogen chloride (2.4 g,0.014 mol) and the mixture was heated to 180° C. for 1.5 h. The mixturewas cooled and poured into methanol (4 mL), then filtered. The collectedsolid was further washed with ethyl acetate and dried to give7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one (350 mg,82.7%) as an HCl salt. Selected data: MS (ES) m/z: 266; MP>350° C.

Example 9

3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one

To a solution of 3,5-dimethyl-4-hydroxy benzonitrile (1.0 g, 6.79 mmol)in DMF (100 mL), were added a NaH (1.065 g, 26.63 mmol) and(2-bromoethoxy)-tert-butyl dimethyl silane (1.95 g, 8.15 mmol). Thereaction mixture was stirred for 10 d at room temperature undernitrogen. The reaction mixture was poured into ice-water and theproducts were extracted with ethyl acetate. The organic layer wasseparated, washed with water, dried and concentrated to give crudeproduct, which was purified by column chromatography to give 1.9 g ofthe B-ring building block in 92% yield.

n-Butyl lithium (2.84 mL, 7.1 mmol, 2.5 M solution in hexane) was addedslowly to a solution of 2,4-dimethoxy-6-methyl benzamide (650 mg, 3.1mmol) in THF (30 mL), under nitrogen with cooling (ice-salt bath),maintaining the temperature below 20° C. After completion of addition,the mixture was stirred for 1 h at 0° C., and then cooled to −50° C. anda solution of 4-(2-tert-butyldimethyl silanyloxy)ethoxy)-3,5-dimethylbenzonitrile (the B-ring building block, above) (996 mg, 3.26 mmol) inTHF (10 mL) was added quickly. The cooling bath was removed and thereaction mixture was allowed to warm to room temperature and was stirredfor 16 h at room temperature. A saturated NH₄Cl solution was added withcooling, and the layers were separated. The organic layer was washedwith water, brine, dried over Na₂SO₄ and concentrated to give 1.2 g ofcrude product.

The above crude product (1.2 g) was treated with ethanol (10 mL) andconc. HCl (2 mL) at 80° C. for 1 h. The solvent was removed and theresidue was dissolved in methanol and neutralized by NaHCO₃. The solventwas evaporated and crude product was purified by column chromatographyto give3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one(100 mg, 11%). Selected data: MP 193-195° C.

Example 10

3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one

In a 250 mL round-bottomed flask were placed3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol), Ph₃P (1.96 g,7.47 mmol), diisopropylethylamine (1.75 g, 13.59 mmol) and2-dimethylaminoethanol (660 mg, 7.47 mmol) in THF (30 mL). DEAD (1.42 g,8.15 mmol) was added drop-wise at room temperature. The reaction mixturewas stirred for 48 h at room temperature and water was added and themixture was extracted with ethyl acetate. The combined organic layerswere washed with water, brine and dried over Na₂SO₄ and concentrated togive crude product. The crude product was purified by columnchromatography to give 1.17 g (79%) of the B-ring building block.

n-Butyl lithium (4.2 mL, 10.54 mmol, 2.5 M solution in hexane) was addedslowly to a solution of 2,4-dimethoxy-6-methyl benzamide (958 mg, 4.58mmol) in THF (30 mL) under nitrogen with cooling (ice-salt bath),maintaining the temperature below 20° C. After completion of theaddition, the mixture was stirred for 1 h at 0° C., then cooled to −50°C. and a solution of 4-(2-dimethylamino ethoxy)-3,5-dimethylbenzonitrile (1.1 g, 5.04 mmol) (the B-ring building block) in THF (10mL) was added quickly. The cooling bath was removed and the reactionmixture was allowed to warm to room temperature and stirred for 16 h atroom temperature. A saturated NH₄Cl solution was added with cooling andthe layers were separated. The organic layer was washed with water,brine, dried over Na₂SO₄ and concentrated to give crude product. Thecrude product was purified by chromatography to give3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one(162 mg, 8%) as a hydrochloride. Selected data: MS (ES) m/z: 397.06; MP261-263° C. at decomposition (HCl).

Example 11

3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one

Hydrogen bromide in acetic acid (13 mL, 33 wt %) was added to a mixtureof 2-methyl benzoic acid (4.08 g, 30 mmol), paraformaldehyde (2.50 g,83.0 mmol), and o-phosphoric acid (7 mL, 85%). The reaction mixture wasstirred at 115° C. for 15 h. It was cooled to room temperature andpoured into ice-cold water. A white precipitate was formed. The mixturewas extracted with ethyl acetate (300 mL). The organic layer was washedwith water (100 mL), brine (100 mL) and dried over anhydrous Na₂SO₄.Removal of solvent gave 6.84 g of a white solid, which was used in thenext step without further purification. The above compound (6.8 g) wasdissolved in anhydrous dichloromethane (150 mL). Oxalyl chloride (7.8mL) was added drop-wise. After the addition was complete, 3 drops ofanhydrous DMF were added. A vigorous reaction occurred and the stirringwas continued overnight. Solvent and excess oxalylchloride were removedunder reduced pressure and the residue was dried under vacuum to give7.02 g of brown liquid, which was used in the next step without furtherpurification. The above compound (7.02 g, 28.36 mmol) was dissolved inanhydrous THF (60 mL) and cooled to 0° C. A solution of N-methylamine(2.0 M in THF, 19 mL, 38.03 mmol) was added drop-wise under nitrogen.The stirring was continued for 15 min at 0° C. The ice-bath was removed,and the stirring was continued at room temperature for 3 h. A whiteprecipitate was formed. Water (100 mL) was added and the mixture wasextracted with ethyl acetate (150 mL). The organic layer was separated,washed with water (50 mL), saturated NaHCO₃ solution (2×50 mL), water(50 mL), and brine (50 mL), and dried over anhydrous Na₂SO₄. Removal ofsolvent gave 5.64 g of 5-bromomethyl-2,N-dimethylbenzamide as a whitesolid which was used in the next step without further purification. To asolution of the above compound (2.42 g, 10 mmol) in anhydrous THF wasadded morpholine (1.92 g, 22 mmol) at room temperature under nitrogen. Awhite precipitate was formed. Stirring continued overnight. Water (100mL) was added and the mixture was extracted with ethyl acetate (150 mL).The organic layer was separated, washed with water (50 mL) and brine (50mL) and dried (Na₂SO₄). Removal of solvent gave a colorless oil, whichwas purified by column chromatography (silica gel 230-400 mesh; 0-5%methanol in CH₂Cl₂ as eluent) to give the desired benzamide intermediate(yield 0.50 g, 20%). N-Butyl lithium (1.6 M solution in hexanes, 4.1 mL,6.6 mmol) was added drop-wise to a solution of the benzamide (0.5 g, 2.0mmol) in anhydrous THF (4 mL) at −10° C. over a period of 10 min undernitrogen. Stirring was continued at 0° C. for 1 h. The reaction mixturewas cooled to −50° C. A solution of4-(tert-butyldimethylsilanyloxy)-3,5-dimethylbenzonitrile (0.653 g, 2.5mmol) in anhydrous THF (3 mL) was quickly added. The cooling bath wasremoved and the reaction mixture was allowed to warm to roomtemperature. Stirring was continued at room temperature for 1 h. Anaqueous ammonium chloride solution (5 mL) was added followed by ethylacetate (50 mL). The organic layer was separated, washed with water (5mL) and dried (Na₂SO₄). Removal of the solvent gave 1.23 g pale yellowgummy material, which was used in next step without furtherpurification. The above compound (1.2 g) was dissolved in 10 mLanhydrous ethanol. Conc. HCl (1 mL) was added and the mixture wasrefluxed for 15 min, then cooled to room temperature. The solvent wasremoved under reduced pressure. The crude compound was basified withmethanolic ammonia and purified by column chromatography (silica gel230-400 mesh; 0-5% methanol in CH₂Cl₂ as eluent) to give3-(4-hydroxy-3,5-dimethylphenyl)-7-morpholin-4-ylmethyl-2H-isoquinolin-1-one(35 mg) as a white solid (the free base). To a solution of the abovecompound (35 mg) in CH₂Cl₂ (5 mL) and MeOH (1 mL) was added drop-wisehydrogen chloride in ether (0.5 mL, 1.0 M) under nitrogen. The reactionmixture was stirred at room temperature for 1 h. The solvent was removedunder reduced pressure and dried under vacuum to give the hydrochlorideof3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one(36 mg, 93%) as a yellow solid. Selected data: MP 281-283° C.(hydrochloride).

Example 12

2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-naphthyridin-5(6H)-one

A mixture of malonic acid (20 g, 192 mmol), 2,4,6-trichlorophenol (72 g,365 mmol), and phosphorus oxychloride (38 mL, 403.2 mmol) was stirred atreflux for 12 h. The reaction mixture was cooled to 70° C. and pouredinto ice water. The solid was collected by filtration, washed withwater, and air-dried to give malonic acid bis-(2,4,6-trichloro-phenyl)ester (85 g, 95%). A solution of malonic acidbis-(2,4,6-trichloro-phenyl) ester (85 g, 183.6 mmol) and ethyl3-aminocrotonate (26.1 g, 202 mmol) in bromobenzene (100 mL) was stirredat reflux for 50 min. The reaction mixture was cooled to 50° C. anddiluted with EtOAc (260 mL). The solid was collected by filtration,washed with water, and air-dried, to give 4,6-dihydroxy-2-methylnicotinic acid ethyl ester (31 g, 86%).

A solution of 4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g,157 mmol) in phosphorus oxychloride (60 mL, 629 mmol) was stirred atreflux for 1.5 h. The extra phosphorus oxychloride was removed and thereaction mixture was poured into ice water. The solid was removed byfiltration. The filtrate was extracted with dichloromethane (3×100 mL)and concentrated. The residue was further purified by columnchromatography to yield 4,6-dichloro-2-methyl nicotinic acid ethyl ester(16.9 g, 46%). A solution the ester (16.9 g, 71.3 mmol) in MeOH (60 mL)was mixed with sodium methoxide (58 mL, 257 mmol) and stirred at refluxfor 12 h. The reaction was quenched by adding AcOH (50 mL), diluted withwater (200 mL), extracted with dichloromethane (3×100 mL), andconcentrated. The residue was purified by column chromatography to yield4,6-dimethoxy-2-methyl nicotinic acid methyl ester (10 g, 67%). Asolution of the ester (2.6 g, 12.3 mmol), lithium hydroxide (1.06 g,44.1 mmol) in water (40 mL), MeOH (30 mL) and THF (20 mL) was stirred atreflux for 4 h. The reaction mixture was concentrated to dryness. Theresidue was mixed with HCl (conc., 20 mL) and was concentrated todryness to yield crude 4,6-dimethoxy-2-methyl nicotinic acid(quantitative). To a solution of 4,6-dimethoxy-2-methyl nicotinic acid(2.5 g, 12.0 mmol) in dichloromethane (50 mL) and THF (50 mL) at roomtemperature was added oxalyl chloride (2.57 mL, 29.4 mmol) and DMF (3drops). The reaction mixture was stirred at room temperature for 0.5 h,concentrated to afford 4,6-dimethoxy-2-methyl nicotinic acid chlorideHCl salt (2.8 g). A solution of 4,6-dimethoxy-2-methyl nicotinic acidchloride HCl salt (8.5 g, 33.73 mmol) in dichloromethane (20 mL) and THF(20 mL) at room temperature was mixed with methylamine in THF (50 mL, 98mmol) and stirred at 20° C. for 1 h. The reaction mixture was dilutedwith water (100 mL), extracted with dichloromethane (3×100 mL), andconcentrated to yield 4,6-dimethoxy-2,N-dimethyl-nicotinamide (4.2 g,66%) as a light yellow solid. A solution of4-hydroxy-3,5-dimethylbenzonitrile (2 g, 13.6 mmol) in DMF (20 mL) atroom temperature was mixed with sodium hydride (0.706 g, 17.6 mmol) andstirred for 0.5 h. Benzyl bromide (1.62 mL, 13.59 mmol) was then addedand the reaction mixture was stirred at room temperature for 24 h. Thereaction was quenched by adding water (200 mL), extracted with EtOAc(3×100 mL), and concentrated. The residue was purified by columnchromatography to yield 4-benzyloxy-3,5-dimethylbenzonitrile (3.25 g,100%), as a white solid. To a solution of4,6-dimethoxy-2,N-dimethyl-nicotinamide (0.54 g, 2.57 mmol) in THF (50mL) at −20° C. was added n-BuLi (3.54 mL, 5.67 mmol). The reaction wasstirred at −20° C. to 0° C. for 2 h and then was cooled to −78° C.4-Benzyloxy-3,5-dimethylbenzonitrile (0.49 g, 2.057 mmol) was added, thecooling bath was removed, and the reaction was allowed to warm to roomtemperature. After 14 h, the reaction was quenched by adding water (100mL), extracted with dichloromethane (3×100 mL), and concentrated. Theresidue was purified by column chromatography to yield7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one(0.32 g, 37%). A solution of7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one(0.25 g, 0.6 mmol) in dichloromethane (100 mL) was mixed with BBr₃ (3mL, 3 mmol) and stirred at room temperature for 16 h. The reaction wasquenched by adding water (20 mL). The resulting solid was collected byfiltration, washed with water and DCM, to yield a light yellow solid.This solid was mixed with HCl in ether (10 mL, 10 mmol), stirred for 1h, and filtered to afford2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-naphthyridin-5(6H)-onehydrochloride (70 mg, 37%) as a light yellow solid. Selected data: MS(ES) m/z: 312; MP>330° C. (hydrochloride).

Example 13

2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) ina 5 L 3-necked flask was cooled to 0° C. HCl gas (227 g) was bubbledthrough the solution over 45 min. After 45 min at 10° C., the mixturewas filtered, washed with isopropylacetate (4 L), and dried overnight onhigh vacuum at 45° C. to give the hydrochloride (242.3 g, 98%), as awhite solid. A mixture of the hydrochloride above (20 g, 0.105 mol) andoxalyl chloride (33 mL) in a 3-necked flask equipped with a refluxcondenser was heated for 2 h with stirring (1700° C. externaltemperature), and the oxalyl chloride was distilled from the reactionmixture. The flask was cooled to 0° C. and methanol (40 mL) was added.The reaction mixture was heated to reflux for 45 min, filtered whilehot, and washed with methanol (80 mL) to give the 4,6-dimethoxyisatin(17.2 g, 79%) as a yellow-green solid. To a heated solution (externaltemp 70° C.) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40%, 1.5L) was added H₂O₂(35%, 405 mL) slowly over 2 h-After the addition ofeach portion of H₂O₂, the internal reaction temperature (initially 64°C.) increased (to a maximum temp of 80° C.). After the addition wascomplete, the foaming reaction mixture was then stirred for anadditional 2 h at 70′C, and the mixture was allowed to stir overnightwhile cooling to room temperature. The mixture was heated to 70° C.Additional H₂O₂(75 mL) was added, and the mixture was stirred at 70° C.for a further 2 h until the reaction was complete. After cooling to 10°C. (bath temperature), aqueous Na₂S₂O₃ (150 mL, saturated) was added.The mixture was brought to pH 8 with HCl (37%, 1.6 L) and pH 6 withacetic acid (glacial, 75 mL), without allowing the reaction mixture towarm to greater than 40° C. Filtration of the reaction mixture andwashing with water (4 L) gave the expected amino acid as a tan solid(83.7 g, 55%). To a solution of the amino acid (82.7 g, 0.42 mol) inanhydrous THF (4.2 L) was added EDCl (89.2 g, 0.48 mol), HOBT (65 g,0.48 mol), and NMM (51.3 mL), and the mixture was allowed to stir atroom temperature for 3 h. Aqueous NH₃ (83 mL, 50%) was added, and themixture was stirred at room temperature for 16 h. Water (1.25 L) wasadded, and the mixture was extracted with DCM (2×250 mL). The combinedextracts were then washed with water (2×500 mL). Concentration,formation of a slurry with ether (550 mL), filtration, and drying underhigh vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g, 57%) as a brownsolid.

2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol),3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K₂CO₃ (0.747 g,5.4 mmol) and I₂ (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and thereaction mixture was heated at 80° C., for 12 h. It was cooled to roomtemperature and poured into crushed ice. The solid was collected andpurified by column chromatography to give2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9g, 51%) as a white solid. Selected data: MP 291-293° C.

Example 14

3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one

To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.5 mmol)and 1-chloro-2-methyl propan-2-ol (8.85 g, 81.5 mmol) in ethanol (50 mL)was added potassium carbonate (7.5 g, 54 mmol) and water (5 mL). Thereaction mixture was stirred at reflux for 24 h and cooled to roomtemperature. The precipitated solid was filtered off and washed withwater. The solid was dissolved in ethyl acetate (100 mL), washed withwater (50 mL), brine (50 mL), and dried over anhydrous Na₂SO₄. Removalof solvent gave 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile(2.9 g, 97%) as a white solid.

To a solution of 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile(2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g,40 mmol) and tert-butyldimethylsilylchloride (2.19 g, 14.6 mmol). Thereaction mixture was stirred at room temperature under nitrogen for 3 d.Water (200 mL) was added and the mixture was extracted with ethylacetate (200 mL). The organic layer was washed with water (2×100 mL) andbrine (100 mL), and dried over anhydrous Na₂SO₄. The solvent was removedunder reduced pressure and the crude compound was purified by columnchromatography to give4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile(2.24 g, 54%). N-Butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution inhexanes) was added to a solution of 2,4-dimethoxy-6-N-dimethylbenzamide(0.9 g, 4.3 mmol) in anhydrous THF (10 mL) drop-wise at −10° C. over aperiod of 10 min under nitrogen. The stirring was continued at 0° C. for1 h. The reaction mixture was cooled to −50° C. A solution of4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile(1.58 g, 4.73 mmol) in anhydrous THF (5 mL) was quickly added. Thecooling bath was removed and the reaction mixture was allowed to warm toroom temperature. The stirring was continued at room temperature for 1h. An aqueous ammonium chloride solution (10 mL) was added followed byethyl acetate (100 mL). The organic layer was separated, washed withwater (10 mL) and dried (Na₂SO₄). The solvent was removed under reducedpressure and the crude compound was purified by column chromatography(silica gel 230-400 mesh; 0-5% methanol in CH₂Cl₂ as eluent) to give3-{4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylphenyl}-6,8-dimethoxy-2H-isoquinolin-1-one(0.82 g, 37%), as a white solid.

The above compound (0.42 g, 0.82 mmol) was dissolved in anhydrous THF(20 mL). Tetrabutylammonium fluoride (4.1 mL, 1.0 M solution in THF) wasadded at 0° C. The reaction mixture was stirred at 0° C. for 10 min,then at room temperature for 2 h and then stirred at 70° C. for 24 h.The mixture was cooled to room temperature. Saturated aqueous ammoniumchloride (30 mL) was added. The organic layer was separated, washed withwater, brine, and dried over anhydrous Na₂SO₄. The solvent was removedunder reduced pressure. The crude product was purified by columnchromatography (silica gel 230-400 mesh; 0-4% methanol in CH₂Cl₂ aseluent) to give3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one(0.15-g, 46%), as a white solid. Selected data: MS (ES) m/z: 397.98; MP252-254° C. at decomposition.

Example 15

6,8-dimethoxy-3-(4-hydroxy-3,5-dimethylphenyl)-2H-1,2-benzothiazine-1,1-dioxide

To a 3-necked, round-bottomed flask was added 3,5-dimethoxytoluene(6.088 g, 40 mmol) and cyclohexane (28 mL) under nitrogen. Dimethylcarbonate (30.3 g, 336 mmol) was added and the reaction mixture washeated at 60° C. Excess chlorosulfonic acid was added over a period of15 min. The liberated HCl gas was removed by inserting a tube into solidsodium hydroxide. On completion of the addition, the reaction mixturewas heated to 70-72° C. for 1 h and then cooled to room temperature. Thesolid was filtered off and washed with dimethyl carbonate/cyclohexane(1:1, 20 mL). The solid was dried in vacuo to obtain pure material (6.13g, 66%). To a mixture of the sulfonic acid (product from above, 4.65 g,20 mmol) and triethyl amine (2.03 g, 2.79 mL) in acetone (40 mL) wasadded 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride, 3.69 g, 20mmol). The reaction mixture was heated under reflux for 20 h beforebeing cooled to room temperature. The solution was passed through aCelite pad and evaporated in vacuo to leave a solid, which was filteredoff and washed with hexane. The mixture of product and salt of cyanurichydroxide and triethyl amine (7.58 g) was used for the next step withoutfurther purification.

To a 3-necked, round-bottomed flask, equipped with a condenser(acetone-dry ice cooling), was added the mixture from the step above(7.58 g) and acetone (100 mL). The reaction mixture was cooled to −78°C. and ammonia gas was bubbled through the solution for 0.5 h. Thereaction mixture was kept standing overnight, allowing slow evaporationof ammonia gas, followed by the evaporation of solvent. Water was addedand the product was extracted with DCM. The solvent was dried andevaporated to leave a mixture of solid and a dense liquid. The solid wasfiltered off and washed with hexane to leave pure sulfonamide (3.23 g,70%).

To a round-bottomed flask was added 3,5-dimethyl-4-hydroxybenzoic acid(2.99 g, 18 mmol). Anhydrous DMF (20 mL) was added, followed by sodiumhydride (1.8 g, 45 mmol). The reaction mixture was stirred at roomtemperature for 1 h. p-Methoxybenzyl chloride (6.20 g, 39.6 mmol) wasadded and the mixture was stirred at room temperature overnight (˜20 h).The reaction mixture was poured into water, acidified with 1 N HCl andstirred for 1 h. The precipitated solid was filtered off, washed withwater and hexane to obtain pure B-ring building block (6.93 g, 95%).

The B-ring building block (6.93 g, 17.1 mmol) was dissolved in a mixtureof methanol (50 mL) and tetrahydrofuran (50 mL). Potassium hydroxide(1.25 g, 22.2 mmol) in water (20 mL) was added. The reaction mixture wasrefluxed at 70° C. for 24 h. The solvent was evaporated in vacuo. Waterwas added and the reaction mixture was acidified with 1 N HCl (pH 4-5).The solid was filtered off, washed with water and hexane. The yield was4.61 g (94%). The product (1.932 g, 6.75 mmol) and the sulfonamide fromabove (1.04 g, 4.5 mmol) were taken in a 3-necked, round-bottomed flaskunder nitrogen. Dichloromethane (100 mL) was added with stirring. Tothis stirred mixture was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCl. HCl,1.36 g, 7.09 mmol), followed by N,N-dimethylaminopyridine (2.06 g, 16.9mmol). The reaction mixture was stirred at room temperature for 24 hbefore being washed with 1 N HCl, 2.5% NaOH and saturated sodiumbicarbonate solutions. The organic layers were dried and evaporated invacuo to leave a residue, which was purified by silica gel (100 g)column chromatography, employing 20-50% ethyl acetate in hexane and 5%methanol in dichloromethane as eluents. Fractions 30-66 were combined toobtain pure materials (1.35 g, 60%). The compound from the step above(0.105 g, 0.21 mmol) was dissolved in tetrahydrofuran under nitrogen andcooled to −78° C. n-Butyllithium was added and the reaction mixture wasallowed to warm to room temperature slowly and stirred overnight (˜14h). TLC showed incomplete conversion. The reaction mixture was quenchedwith saturated ammonium chloride solution and extracted with ethylacetate. The solvent was evaporated in vacuo to leave a residue that waspurified by silica gel (15 g) column chromatography, employing 20-50%ethyl acetate in hexane as eluents. The product was not pure enough, soanother column was used, employing 0.5% methanol in hexane as eluent,and finally preparative TLC was employed to purify the material. Thecompound from the step above (0.277 g) was dissolved in trifluoroaceticacid (10 mL) under nitrogen and the reaction mixture was refluxed (bathtemperature 80° C.) for 4 d. The solvent was evaporated in vacuo and theresidue was dissolved in 0.25 N NaOH (20 mL), and acidified with aceticacid. The solid had precipitated out at this point. The solid wasfiltered off and washed with water, hexane and dried. From one batch,0.005 g of pure material was isolated. From another batch, 0.060 gcompound was isolated, which was not pure enough. This compound wasfurther purified by preparative HPLC to give pure6,8-dimethoxy-3-(4-hydroxy-3,5-dimethylphenyl)-2H-1,2-benzothiazine-1,1-dioxide(0.010 g). Selected data: MP 246.6-247.4° C.

Example 16

7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one

A mixture of malonic acid (20 g, 192 mmol), 2,4,6-trichlorophenol (72 g,365 mmol), and phosphorus oxychloride (38 mL, 403.2 mmol) was stirred atreflux for 12 h. The reaction mixture was cooled to 70° C. and pouredinto ice water. The solid was collected by filtration, washed withwater, and dried to give malonic acid bis-(2,4,6-trichloro-phenyl) ester(85 g, 95%). A solution of malonic acid bis-(2,4,6-trichloro-phenyl)ester (85 g, 184 mmol) and ethyl 3-aminocrotonate (26.08 g, 201.9 mmol)in bromobenzene (100 mL) was stirred at reflux for 50 min. The reactionmixture was cooled to 50° C. and diluted with EtOAc (260 mL). The solidwas collected by filtration, washed with water, and dried to give4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 86%). Asolution of 4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 157mmol) in phosphorus oxychloride (60 mL, 629 mmol) was stirred at refluxfor 1.5 h. The extra phosphorus oxychloride was removed and the reactionmixture was poured into ice water. The solid was removed by filtration.The filtrate was extracted with dichloromethane (3×100 mL) andconcentrated. The residue was further purified by column chromatography,to yield 4,6-dichloro-2-methyl nicotinic acid ethyl ester (16.9 g, 46%).A solution of 4,6-dichloro-2-methyl nicotinic acid ethyl ester (16.9 g,71.3 mmol) in MeOH (60 mL) was mixed with sodium methoxide (58 mL,256.68 mmol) and stirred at reflux for 12 h. The reaction was quenchedby adding HOAc (50 mL). The mixture was diluted with water (200 mL),extracted with dichloromethane (3×100 mL), and concentrated. The residuewas purified by column chromatography (SiO₂, hexanes/EtOAc=6:1), toyield 4,6-dimethoxy-2-methyl nicotinic acid methyl ester (10 g, 67%). Asolution of 4,6-dimethoxy-2-methyl nicotinic acid methyl ester (2.6 g,12.3 mmol), lithium hydroxide (1.06 g, 44.08 mmol) in water (40 mL),MeOH (30 mL) and THF (20 mL) was stirred at reflux for 4 h. The reactionmixture was concentrated to dryness. The residue was mixed with HCl(conc., 20 mL) and was concentrated again on high vacuum to dryness toyield crude 4,6-dimethoxy-2-methyl nicotinic acid (quantitative yield).To a solution of 4,6-dimethoxy-2-methyl nicotinic acid (2.5 g, 12.0mmol) in dichloromethane (50 mL) and THF (50 mL) at room temperature wasadded oxalyl chloride (2.57 mL, 29.4 mmol) and DMF (3 drops). Thereaction mixture was stirred at room temperature for 0.5 h, concentratedto dryness using a rotary evaporator to afford crude4,6-dimethoxy-2-methyl nicotinic acid chloride HCl salt (2.8 g,quantitative). A solution of 4,6-dimethoxy-2-methyl nicotinic acidchloride HCl salt (4.8 g, 23.5 mmol) in dichloromethane (100 mL) at roomtemperature was poured into a beaker of ammonium hydroxide (200 mL). Thereaction mixture was stirred at room temperature for 1 h, extracted withdichloromethane (3×100 mL), and concentrated using a rotary evaporatorto yield 4,6-dimethoxy-2-methyl-nicotinamide (2.4 g, 52%) as a lightyellow solid. A solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g,13.59 mmol) in DMF (20 mL) at room temperature was mixed with sodiumhydride (0.706 g, 17.6 mmol) and stirred for 0.5 h. Benzyl bromide (1.62mL, 13.59 mmol) was added and the reaction mixture was stirred at roomtemperature for 24 h. The reaction was quenched by adding water (200mL), extracted with EtOAc (3×100 mL), and concentrated. The residue waspurified by column chromatography to yield4-benzyloxy-3,5-dimethylbenzonitrile (3.25 g, 100%) as a white solid. Toa solution of 4,6-dimethoxy-2-methyl-nicotinamide (1 g, 5.1 mmol) in THF(120 mL) at −20° C. was added n-BuLi (9.6 mL, 15.3 mmol). The reactionwas stirred at −20-0° C. for 2.5 h and then was cooled to −78° C.4-Benzyloxy-3,5-dimethylbenzonitrile (1.21 g, 5.1 mmol) was added, thecooling bath was removed, and the reaction was allowed to warm upgradually to room temperature. After stirring at room temperature for 20h the reaction was quenched by adding water (100 mL), extracted withdichloromethane (3×100 mL), and concentrated using a rotary evaporator.The residue was further purified by column (SiO₂,Hexanes/EtOAc/MeOH=3:2:1) to yield7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-[1,6]naphthyridin-5-ylamine(0.4 g, 19%) and7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one(0.34 g, 16%). A solution of7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one(0.34 g, 0.82 mmol) in DMF (100 mL) and MeOH (100 mL) was mixed withpalladium/carbon (0.1 g) and subjected to hydrogenation (50 psi) for 2h. The mixture was filtered through a Celite-pad. The filtrate wasconcentrated on high vacuum to afford7-(4-hydroxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one(0.23 g, 88%). A solution of7-(4-hydroxy-3,5-dimethyl-phenyl)-2,4-dimethoxy-6H-[1,6]naphthyridin-5-one(0.23 g, 0.7 mmol) in MeOH (20 mL) and DCM (20 mL) was mixed with HCl inether (7 mL, 7 mmol) and stirred for 0.5 h. The reaction wasconcentrated using a rotary evaporator to get a solid residue. The solidwas rinsed with DCM, collected by filtration, washed with DCM to yieldthe HCl salt of7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one(0.15 g, 59%) as a light yellow solid. Selected data: MS (ES) m/z:327.06; MP>324° C. at decomposition (HCl salt).

Example 17

3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one(left) And3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholinomethyl)isoquinolin-1(2H)-one(right)

Methyl acetoacetate (69.67 g, 0.6 mol) in dry THF (350 mL) was cooled to−5° C. and sodium hydride (60% in mineral oil, 24.5 g) was added at −5to 0° C. in 30 min. Diketene (50.4 g) in dry THF (80 mL) was then addeddrop-wise at 5° C. over 20 min. The resulting solution was allowed tostir for 1 h at −5° C., after which it was allowed to warm to roomtemperature and stirred overnight. Acetic acid (35 mL) was added and theTHF solvent was removed. Water (200 mL) and ethyl acetate (300 mL) wasadded to the residue, pH was adjusted to 5.0 by adding HCl solution. Theorganic layer was separated and washed with brine and dried over sodiumsulfate. After column purification and recrystalization, compound A(methyl 2,4-dihydroxy-6-methylbenzoate) was obtained (yield: 26.6 g,24.3%). Sodium hydride (11.2 g, 0.279 mol, 60% in mineral oil) was addedto compound A (24.8 g, 0.136 mol) in DMF (150 mL). The reactiontemperature was cooled to −30° C. and methyl iodide (21.3 mL, 0.341 mol)was added and the reaction was kept at room temperature overnight.Sodium iodide was filtered off and DMF was removed. The residue wasmixed with water (100 mL) and extracted with ethyl acetate. The organiclayer was further washed with brine and dried over sodium sulfate. Thecrude mixture was purified by column chromatography to yield compound B(11.40 g, 39.9%). To a solution of compound B (11.4 g, 0.054 mol) in dryCCl₄ (90 mL) was added N-bromosuccinimide (10.6 g, 0.0596 mol). Themixture was refluxed overnight. CCl₄ was removed. Water (100 mL) wasadded to the residue and the solid was filtered off and washed withwater and a mixture of ethyl acetate (10 mL) and hexane (30 mL) to yieldcompound C (13.1 g, 83.9%). Compound C (12.5 g, 0.043 mol), chloromethylmethyl ether (81.0 g) and anhydrous zinc chloride (7.0 g, 0.0513 mol)was kept at room temperature overnight. Chloromethyl methyl ether wasremoved and the residue was mixed with water and the pH was adjusted to7 by adding sodium bicarbonate. The mixture was extracted with ethylacetate and the organic layer was washed with brine and dried oversodium sulfate. Compound D (7.39 g, 50.6%) was obtained after columnchromatography. Compound D (7.39 g, 0.0218 mol), morpholine (7.62 g,0.0875 mol), and anhydrous THF (20 mL) were stirred at room temperatureovernight. The solvent was evaporated. Water and ethyl acetate wereadded to the residue, pH was adjusted to 9.0 with sodium bicarbonate.The organic layer was washed with brine and dried with sodium sulfate.Compound E (5.4 g, 63.8%) was obtained after column chromatography. Thehydrogenation reaction was carried out at 50 psi with compound E (5.4 g,0.0139 mol) in THF (100 mL) and triethyl amine (3.9 mL) with Pd/C (10%,2.6 g) as a catalyst for 2 d. After the catalyst was filtered off, theorganic layer was purified by column chromatography to yield compound F(3.20 g, 74.4%) and 1.1 g starting material E. Compound F (3.20 g,0.0103 mol) was dissolved in ethanol (30 mL) and potassium hydroxide(2.31 g, 0.041 mol) in water (20 mL) was added and the reaction mixturewas heated to 100° C. overnight. The solvent was removed, the pH wasadjusted to 6.0 and the water was removed. The residue was further driedunder high vacuum and the compound was extracted with ethanol to yieldcompound G (2.95 g, 99%). Compound G (2.80 g, 0.0095 mol) was mixed withthionyl chloride (7.0 mL, 0.0108 mol) and heated to reflux for 1 h.Excess thionyl chloride was removed and the residue was further driedunder high vacuum and anhydrous THF (20 mL) was added and methylamine inTHF (2.0 M, 30 mL) was added and the reaction was stirred for overnight.THF was removed and pH was adjusted to 8.0-9.0, the mixture wasextracted with dichloromethane and dried over sodium sulfate to givecompound H (2.50 g, 85.4%).

NaH (1.14 g, 0.0285 mol, 60% in mineral oil) was added to4-hydroxy-3,5-dimethylbenzonitrile (4.0 g, 0.027 mol) in anhydrous DMF(20 mL), followed by benzyl bromide (3.27 mL, 0.027 mol). The reactionwas kept at room temperature overnight. The reaction mixture was pouredinto water and the solid was filtered off and washed with hexane toyield compound I (5.7 g, 89%). Compound I was used for the next stepwithout further purification.

n-BuLi (1.60 M, 3.3 mL) was added drop-wise to compound H (0.25 g, 0.81mmol) in anhydrous THF (25 mL) at −10° C. The reaction mixture was keptat 0° C. for 1 h then the cool bath was removed and the reaction mixturewas further stirred for 45 min. Compound I (0.192 g, 0.81 mmol) inanhydrous THF (5 mL) was added drop-wise at −10° C. and the reaction wasfurther kept for 30 min; the reaction temperature was increased to roomtemperature and the reaction mixture was stirred for a further 1 h.Water (20 mL) was added and the mixture was extracted with ethylacetate. The solvent was removed and the residue was treated with aceticacid at 65° C. for 30 min then purified by column chromatography toyield compound J (0.110 g, 25.9%). Product J (300 mg) in methanol (80mL) and 10% Pd/C (100 mg) as catalyst was stirred under H₂ (50 psi) for1 h. The catalyst was filtered off and the solvent was removed. Theresidue was purified by column chromatography (10% methanol in ethylacetate) to yield3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one(60 mg, 29.8%) and3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholinomethyl)isoquinolin-1(2H)-one(40 mg, 16.8%). Selected data for3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one:MP 246-248° C. Selected data for3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholinomethyl)isoquinolin-1(2H)-one:MP 224-225° C.

Example 18

4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol

Phosphorousoxychloride (10 mL, 109.24 mmol) was added drop-wise at 0° C.to a stirred solution of 1-bromo-3,5-dimethoxy benzene (9.1 g, 41.9mmol) in anhydrous DMF (40 mL). The reaction mixture was stirred at 0°C. for 10 min and then at room temperature for 30 min, then at 100° C.for 4 h. The reaction mixture was cooled to room temperature, pouredinto ice-cold water and kept overnight. A solid precipitated and wasfiltered off, washed with water and dried under vacuum to give2-bromo-4,6-dimethoxy benzaldehyde (8.67 g, 84%) as a yellow solid. To asolution of 4-bromo-2,6-dimethylphenol (6.03 g, 30 mmol) in anhydrousDMF (100 mL) was added sodium hydride (60% suspension in mineral oil,1.26 g, 31.5 mmol) in small portions under nitrogen at room temperature.The reaction mixture was stirred for 30 min. Benzyl bromide (5.39 g,31.5 mmol) was added slowly and stirring was continued at roomtemperature for 2 h. Water (200 mL) was added and the mixture wasextracted with hexanes (2×200 mL). The organic layer was washed withwater (3×100 mL) and dried over anhydrous Na₂SO₄. Removal of solventgave 2-benzyloxy-5-bromo-1,3-dimethylbenzene (9.59 g) as a white solidwhich was used in the next step without further purification.(Dichloro)bis(triphenylphosphene)palladium (0.239 g, 0.34 mmol) andcopper (I) iodide (0.065 g, 0.34 mmol) were added to a solution of2-benzyloxy-5-bromo-1,3-dimethylbenzene (4.96 g, 17.03 mmol) andtrimethylsilyl acetylene (1.84 g, 18.74 mmol) in triethyl amine (70 mL).The reaction mixture was stirred at reflux under nitrogen for 4 h. Themixture was cooled to room temperature. The precipitated ammonium saltwas filtered off. The filtrate was concentrated under reduced pressure.The residue was dissolved in hexanes (300 mL) and washed with 2 Naqueous HCl (2×50 mL), water (50 mL), brine (50 mL), and dried overanhydrous Na₂SO₄. Removal of solvent gave a dark brown liquid which waspurified by column chromatography (silica gel 230-400 mesh; 0-5% ethylacetate in hexanes as eluent) to give(4-benzyloxy-3,5-dimethylphenylethynyl)trimethylsilane (4.0 g, 76%yield) of as pale yellow oil. To a degassed solution of(4-benzyloxy-3,5-dimethylphenylethynyl)trimethylsilane (3.96 g, 12.83mmol) in anhydrous THF (60 mL) was added tetrabutylammonium fluoride(38.5 mL, 1.0M solution in THF) at 0° C. under nitrogen. Stirringcontinued at 0° C. for 1 h. A saturated aqueous NH₄Cl solution (100 mL)was added. The reaction mixture was extracted with hexanes (300 mL). Theorganic layer was washed with saturated aqueous NH₄Cl solution and driedover anhydrous Na₂SO₄. The crude compound was purified by columnchromatography to give 2-benzyloxy-5-ethynyl-1,3-dimethylbenzene (2.77g, 91% yield) as a pale yellow oil. To a degassed solution of2-bromo-4,6-dimethoxy benzaldehyde (2.37 g, 9.68 mmol) inDMF-triethylamine (5:1, 95 mL) were addeddichlorobis(triphenylphosphine)-palladium(II) (0.34 g, 0.484 mmol) andcopper(I) iodide (0.553 g, 2.90 mmol). The reaction mixture wasdegassed. To this stirred solution, a degassed solution of2-benzyloxy-5-ethynyl-1,3-dimethylbenzene (2.86 g, 12.1 mmol) inDMF-triethylamine (5:1, 37 mL) was added at 75° C. under nitrogen over aperiod of 3 h. After the completion of the addition, stirring continuedat 75° C. under nitrogen for 4 h. The reaction mixture was allowed tocool to room temperature. Water (200 mL) was added. The mixture wasextracted with ethyl acetate (300 mL). The organic layer was washed withwater (3×150 mL) and brine (150 mL), and dried over anhydrous Na₂SO₄.Removal of solvent gave a black gummy material, which was purified bycolumn chromatography to give2-(4-benzyloxy-3,5-dimethylphenylethynyl)-4,6-dimethoxybenzaldehyde (2.8g, 72% yield) of as a brown solid. Tert-Butylamine (20 mL) was added tothe above compound (2.63 g, 5.772 mmol). The reaction mixture wasstirred under nitrogen for 16 h. Excess tert-butylamine was removedunder reduced pressure. The mixture was dried under vacuum to give 3.11g of imine as a brown solid. To a solution of above imine (3.07 g, 6.738mmol) in anhydrous DMF (160 mL) was added copper (I) iodide (0.123 g,0.674 mmol) and the reaction mixture was stirred at 100° C. for 5 hunder nitrogen and cooled to room temperature. Water (200 mL) was addedand the reaction mixture was extracted with ethyl acetate (2×200 mL).The organic layer was washed with water (2×100 mL), brine (150 mL), anddried over anhydrous Na₂SO₄. Removal of solvent gave a dark brown gummymaterial, which was purified by column chromatography (silica gel230-400 mesh; 0-15% ethyl acetate in hexanes as eluent) to give3-(4-benzyloxy-3,5-dimethylphenyl)-6,8-dimethoxy isoquinoline (0.689 g,26%) as a brown solid. To a solution of3-(4-benzyloxy-3,5-dimethylphenyl)-6,8-dimethoxy isoquinoline (0.68 g,1.70 mmol) in 1:1 methanol-ethyl acetate (40 mL) was added Pd—C(10%, 200mg) and the mixture was hydrogenated for 16 h. After reaction completionthe mixture was filtered through Celite. The filtrate was concentratedand dried under vacuum to give4-(6,8-Dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (0.51 g, 97%) as ayellow solid. To a solution of4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (25 mg, 0.081 mmol)in methanol/CH₂Cl₂ (1:1, 6 mL) was added a solution of hydrogen chloridein ether (1.0 M, 1 mL) and the reaction mixture was stirred at roomtemperature for 15 min. The solvent was removed under reduced pressure.The residue was triturated with ether to give the hydrochloride of4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol (28 mg, 99%) as ayellow solid. Selected data: MP 255-256° C. (HCl salt).

Example 19

3-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one

(3,5-Dimethoxy-phenyl)-acetic acid (10.0 g, 51 mmol) was dissolved inanhydrous methanol (100 mL) and H₂SO₄ (1 mL) was added drop-wise. Thereaction mixture was refluxed overnight and cooled to room temperature.The solvent was removed and the residue was dissolved in ethyl acetateand washed with a NaHCO₃ solution, water and dried (Na₂SO₄). The solventwas evaporated in vacuo to obtain (3,5-dimethoxy-phenyl)-acetic acidmethyl ester in 97% (10.4 g) yield. To a solution of(3,5-dimethoxy-phenyl)-acetic acid methyl ester (10.4 g, 49.5 mmol) indimethyl formamide (40 mL), POCl₃ (5.4 mL, 59.37 mmol) was added at 55°C. After the addition, the reaction mixture was heated at 100° C. for 10min and then stirred at room temperature overnight. The reaction mixturewas poured into ice-water and extracted with ethyl acetate, washed withwater, brine, dried over anhydrous Na₂SO₄ and evaporated in vacuo toobtain (2-formyl-3,5-dimethoxy-phenyl)-acetic acid methyl ester (10.0 g,85%). (2-Formyl-3,5-dimethoxy-phenyl)-acetic acid methyl ester (5.0 g,21 mmol) was dissolved in CH₃CN (100 mL), NaH₂PO₄ (0.655 g, 5.46 mmol)in water (2 mL) and 30% H₂O₂(2.3 mL, 21 mmol). The reaction mixture wascooled to 0° C. and a solution of NaO₂Cl (2.65 g, 29.4 mmol) in water (5mL) was added. The reaction mixture was stirred at room temperature for4 h before being quenched by the addition of Na₂SO₃ solution. Themixture was acidified with 2 N HCl and extracted with ethyl acetate. Thesolvent was evaporated in vacuo to obtain2,4-dimethoxy-6-methoxycarbonylmetyl-benzoic acid (5.25 g, 98%). To asolution of 2,4-dimethoxy-6-methoxycarbonylmetyl-benzoic acid (5.25 g,20.6 mmol) in methanol (50 mL), a solution of NaOH (4.12 g, 103 mmol) inwater (20 mL) was added and the reaction mixture was allowed to stir atroom temperature for 3 h. The solvent was removed, diluted with waterand acidified with 2 N HCl. The compound was extracted with ethylacetate, washed with water, brine, dried over anhydrous Na₂SO₄ andevaporated in vacuo to obtain 2-carboxymethyl-4,6-dimethoxy-benzoic acid(4.65 g, 94%). To a suspension of 2-carboxymethyl-4,6-dimethoxy-benzoicacid (4.65 g, 19.4 mmol) in toluene (50 mL) was added acetic anhydride(2.01 mL, 21.3 mmol) and the reaction mixture was heated to reflux for 2h. After cooling to 0° C., the precipitated solid was filtered off andwashed with heptane and hexane to obtain6,8-dimethoxy-isochroman-1,3-dione (3.56 g, 83%).

To a solution of 3,5-dimethyl-4-hydroxy-benzoic acid (3.0 g, 18.05 mmol)in pyridine (7 mL) was added acetic anhydride (2.05 mL, 21.66 mmol) andthe reaction mixture was stirred at room temperature for 16 h. Water wasadded and the mixture was extracted with ethyl acetate, washed withwater, brine and dried over anhydrous Na₂SO₄. The solvent was evaporatedin vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid (3.52 g, 94%). Toa solution of 4-acetoxy-3,5-dimethyl-benzoic acid (6.02 g, 28.91 mmol)in CH₂Cl₂ (80 mL), oxalyl chloride (5.04 mL, 57.83 mmol) was addedslowly, followed by a drop of dimethyl formamide. The reaction mixturewas stirred at room temperature for 2 h. The solvent was removed andacetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester was dried undervacuum (6.37 g, 97%). To a solution of N,N,N,N-tetramethyl guanidine(2.77 mL, 22.078 mmol) in CH₃CN (50 mL), a solution of6,8-dimethoxy-isochroman-1,3-dione (4.46 g, 20.07 mmol) in CH₃CN (100mL) was added slowly at <0° C. (bath temperature −20° C.) in 30 min.Then, Et₃N was added in one portion, followed by a solution of aceticacid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (6.37 g, 28.1 mmol) inCH₃CN (50 mL) and stirred for 30 min. at <0° C. The reaction mixture wasstirred at room temperature for 16 h, then heated to reflux for 3 h.After cooling to room temperature, the reaction mixture was quenchedwith 1 N HCl. The precipitated solid was filtered off to give a mixtureof acetic acid4-(6,8-dimethoxy-1,3-dioxo-isochroman-4-carbonyl)-2,6-dimethyl-phenylester and acetic acid4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester(6.0 g).

The above mixture (6.0 g) was dissolved in H₂SO₄ (30%, 30 mL) and heatedat 100° C. for 2 h. The reaction mixture was cooled to room temperatureand the precipitated solid was filtered off to obtain a mixture ofacetic acid4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester and3-(4-hydroxy-3,5-dimethyl-phenyl)-6,8-dimethoxy-isochromen-1-one (5.5g). The above mixture (5.5 g) was dissolved in methanol (30 mL), K₂CO₃(3.09 g, 22.4 mmol) and water (10 mL) were added and the reactionmixture was stirred at room temperature for 6 h. The solvent was removedand acidified with dilute HCl. The compound was extracted with ethylacetate, washed with water, brine and dried over anhydrous Na₂SO₄. Thesolvent was evaporated in vacuo to leave a residue which was purified bychromatography (silica gel, 230-250 mesh; 2% methanol indichloromethane) to obtain3-(4-hydroxy-3,5-dimethyl-phenyl)-6,8-dimethoxy-isochromen-1-one. Theyield was 1.462 g.

To a solution of3-(4-hydroxy-3,5-dimethyl-phenyl)-6,8-dimethoxy-isochromen-1-one (0.875g, 2.68 mmol) in DMF (5 mL), NaH (0.129 g, 3.22 mmol) was added and themixture was stirred for 1 h. To the reaction mixture was added1-chloro-2-iodo-ethane (1.23 mL, 13.4 mmol) and stirring was continuedfor 16 h. Then the reaction mixture was heated at 80° C. before beingquenched with 1 N HCl at room temperature. The crude was purified bycolumn chromatography (silica gel, 230-250 mesh; 2% methanol indichloromethane). The yield was 0.36 g (35%). The compound3-[4-(2-chloro-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-isochromen-1-one(0.36 g, 0.927 mmol) was dissolved in DMSO (5 mL), morpholine (0.4 mL,4.63 mmol) and Et₃N (0.64 mL, 4.63 mmol) were added. The reactionmixture was heated at 110° C. for 16 h before being cooled to roomtemperature. Water was added and the compound was extracted with ethylacetate. The solvent was evaporated in vacuo to leave a residue, whichwas purified by chromatography. The yield was 0.128 g (31%). Thecompound3-[3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)-phenyl]-6,8-dimethoxy-isochromen-1-one(0.128 g, 0.29 mmol) and NH₃ (2.0 M solution in ethanol, 30 mL) weremixed in a steel bomb and heated at 130° C. for 16 h. The solvent wasremoved and the crude compound was purified by chromatography (silicagel, 230-250 mesh). The compound was then converted into the HCl salt of3-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one(84 mg, 66%). Selected data: MP 196-198° C. (HCl salt).

Example 20

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (0.856g, 2.78 mmol) in N,N-dimethyl formamide (20 mL) was stirred at 70° C.for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g,2.78 mmol) were added and the reaction mixture was stirred at 70° C. for16 h. The reaction mixture was poured into ice, and extracted with ethylacetate. The organic layer was washed with water, brine, and dried overanhydrous Na₂SO₄. Removal of the solvent gave the crude product whichwas purified by column chromatography to give2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(444 mg, 39%) as a white solid. Selected data: 229-231° C.

Alternatively,2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onecan be synthesized by the following method. In a 2 L dry round-bottomflask with a reflux condenser and magnetic stirrer was placed3,5-dimethyl-4-hydroxy benzaldehyde (26.9 g, 0.179 mol) in ethanol (350mL). 2-chloroethanol (87.6 g, 1.074 mol) and K₂CO₃ (99 g, 0.716 mol)were added and the reaction mixture was heated to reflux for 24 h. Thereaction mixture was cooled to room temperature and filtered. Thesolvent was removed under reduced pressure. The crude product wasdiluted with ethyl acetate and the organic layer was washed with water,brine, and dried over Na₂SO₄. Upon removal of solvent it gave 45 g ofcrude product. The crude product was purified by column chromatography(silica gel 230-400 mesh; 50% ethyl acetate in hexane as eluent) to give33.3 g (95%) of product. To a solution of2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxyethoxy)-3,5-dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethylacetamide (300 mL), NaHSO₃ (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1mmol) were added and the reaction mixture was heated at 150° C. for 14h. The reaction was cooled to room temperature. The solvent was removedunder reduced pressure. The residue was diluted with water and stirredfor 30 min at room temperature. The solids separated were filtered anddried to give crude product. The crude product was purified by columnchromatography (silica gel 230-400 mesh; 5% methanol in CH₂Cl₂ aseluent) to give2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(33 g, 52%).

Example 21

2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

In a 250 mL round-bottomed flask were placed 3,5-dimethyl-4-hydroxybenzaldehyde (4.0 g, 26.7 mmol), Ph₃P (15.38 g, 58.66 mmol),diisopropylethylamine (13.78 g, 106.7 mmol) and 2-morpholin-4-yl-ethanol(7.69, 58.7 mmol) in THF (100 mL), then DEAD (11.1 g, 64 mmol) was addeddrop-wise at room temperature. The reaction mixture was stirred for 3 dat room temperature and water was added and extracted with ethylacetate. The combined organic layers were washed with water, brine anddried over Na₂SO₄ and concentrated to give crude product. The crudeproduct was purified by column chromatography to give the B-ringbuilding block (3.0 g, 43%).

To a solution of 2-amino-4,6-dimethoxybenzamide (451 mg, 2.3 mmol) and3,5-dimethyl-4-(2-morpholin-4yl-ethoxy)-benzaldehyde (550 mg, 2.09 mmol)in N,N-dimethyl formamide (20 mL), iodine (636 mg, 2.5 mmol) andpotassium carbonate (288 mg, 2.09 mmol) were added and the reactionmixture was stirred at 70° C. for 48 h. The reaction mixture was pouredinto ice. The mixture was extracted with ethyl acetate. The organiclayer was washed with water, brine and dried over anhydrous Na₂SO₄.Removal of the solvent gave the crude product was purified by columnchromatography and converted to the hydrochloride salt of2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(40 mg, 4%) as an off-white solid. Selected data: MS (ES) m/z: 440.1; MP185-187° C. (HCl salt).

Example 22

4-(2-(4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)morpholine

To a solution of 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenol(0.309 g, 1.0 mol) in anhydrous THF (20 mL), triphenyl phosphene (0.52g, 2.0 mmol), 4-(2-hydroxyethyl)morpholine (0.262 g, 2.0 mmol) andN,N-diisopropylethylamine (0.387 g, 3.0 mmol) were added. To thisstirred solution was added diethylazodicarboxylate (0.348 g, 2.0 mmol).The reaction mixture was stirred at room temperature overnight undernitrogen, then diluted with ethyl acetate (100 mL). The organic layerwas washed with water and brine, and dried over anhydrous Na₂SO₄. Thesolvent was removed under reduced pressure. The crude material waspurified by column chromatography to give3-[3,5-dimethyl-4-(2-morpholin-4-ylethoxy)phenyl]-6,8-dimethoxyisoquinoline(0.54 g) as a white solid.

To a solution of the above compound (0.54 g, impure) in 1:1 ether-CH₂Cl₂(10 mL), was added 1.0 M solution of hydrogen chloride in ether (2 mL)and the reaction mixture was stirred at room temperature for 30 min.Solvent was removed under reduced pressure. The residue was trituratedwith 10% methanol in ether to give4-(2-(4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)morpholine(0.323 g, 70% over two steps) as a yellow solid. Selected data: MS (ES)m/z: 423.1; MP 239-240° C. (HCl salt).

Example 23

3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one

The compound3-[4-(2-chloro-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-isochromen-1-one(298 mg, 0.767 mmol) was dissolved in DMSO (5 mL) and N-methylpiperazine (388 mg, 3.83 mmol) and Et₃N (392 mg, 3.83 mmol) were added.The reaction mixture was heated at 110° C. for 16 h before being cooledto room temperature. Water was added and the mixture was extracted withethyl acetate. The solvent was evaporated in vacuo to leave a residuewhich was purified by column chromatography. The yield was 60 mg (17%).The compound 3-[3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl-ethoxy)-phenyl]-6,8-dimethoxy-isochromen-1-one (60 mg,0.13 mmol) and NH₃ (2.0 M solution in ethanol, 20 mL) were mixed in asteel bomb and heated at 130° C. for 16 h. The solvent was removed andthe crude compound was purified by column chromatography. The compoundwas then converted to the hydrochloride salt of3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one(40 mg, 62%), an off-white solid. Selected data: MS (ES) m/z: 452.1; MP195-198° C. (HCl salt).

Example 24

2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

2-Amino-4,6-dimethoxy-benzamide (328 mg, 1.67 mmol),4-hydroxybenzaldehyde (204 mg, 1.67 mmol), K₂CO₃ (231 mg, 1.67 mmol) andI₂ (508 mg, 2.0 mmol) were mixed in DMF (10 mL) and the reaction mixturewas heated at 70° C. for 5 h. It was cooled to room temperature andpoured into crushed ice. The solid was collected and purified by columnchromatography (silica gel 230-400 mesh; 5% methanol in CH₂Cl₂ aseluent) to give 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(60 mg, 12%), as an off-white solid. Selected data: MS (m/z): 299.05; MP303-305° C.

Example 25

2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid

2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acidwas synthesized from 2-amino-4,6-dimethoxy-benzamide and (4-formylphenoxy)acetic acid, using the method described for2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one.2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid(135 mg, 21%) was isolated as an off-white solid. Selected data: MS(m/z): 357.04; MP 287-290° C.

Example 26

5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one

To a solution of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.764 mmol) inN,N-dimethyl acetamide (5 mL) were added 2-pyridine carboxaldehyde(0.082 g, 0.764 mmol), sodium hydrogen sulphite (58.5%, 0.15 g, 0.84mmol), and p-toluenesulfonic acid (15 mg, 0.0764 mmol). The reactionmixture was stirred at 1500° C. overnight. The mixture was cooled toroom temperature. Water (40 mL) was added and the reaction mixture wasextracted with dichloromethane (2×50 mL). The combined organic layerswere washed with water and dried over anhydrous Na₂SO₄. The solvent wasremoved and the crude compound was purified by column chromatography(silica gel 230-400 mesh; 1% methanol in CH₂Cl₂ as eluent) to give5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one (0.077 g, 36%) as awhite solid. 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one wasconverted to the corresponding hydrochloride. Selected data: MS (m/z):284.0; MP 215-217° C. (hydrochloride).

Example 27

5,7-dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one

5,7-Dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one was synthesized from2-amino-4,6-dimethoxybenzamide and 3-pyridine carboxaldehyde, using themethod described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.5,7-Dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (105 mg, 48%) wasisolated as a white solid. Selected data: MS (m/z): 284.0; MP 257-259°C. (hydrochloride).

Example 28

2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-onewas synthesized from 2-amino-4,6-dimethoxybenzamide and3,5-di-tert-butyl-4-hydroxybenzaldehyde, using the method described for5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(130 mg, 41%) was isolated as a light yellow solid. Selected data: MS(m/z): 411.17; MP 229.7-230.5° C.

Example 29

2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one wassynthesized from 2-amino-4,6-dimethoxybenzamide and3,5-dimethoxybenzaldehyde, using the method described for5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (120 mg, 46%)was isolated as a yellow solid. Selected data: MS (m/z): 343.05; MP270-272° C.

Example 30

5,7-dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one

5,7-Dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one was synthesizedfrom 2-amino-4,6-dimethoxybenzamide and 4-methoxy benzaldehyde, usingthe method described for5,7-dimethoxy-2-(.pyridin-2-yl)quinazolin-4(3H)-one.5,7-Dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one (106 mg, 44%) wasisolated as an off-white solid. Selected data: MS (m/z): 312.99; MP276-277° C.

Example 31

2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

2-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one wassynthesized from 2-amino-4,6-dimethoxybenzamide and4-hydroxy-3-methoxybenzaldehyde, using the method described for5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (90 mg,36%) was isolated as a white solid. Selected data: MS (m/z): 329.06; MP294-296° C.

Example 32

2-(3-chloro-4-hydroxyphenyl-5,7-dimethoxyquinazolin-4(3H)-one

2-(3-Chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one wassynthesized from 2-amino-4,6-dimethoxybenzamide and3-chloro-4-hydroxybenzaldehyde, using the method described for5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(3-Chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (75 mg,30%) was isolated as a yellow solid. Selected data: MS (m/z): 333.03; MP279-281° C.

Example 33

5,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one

5,7-Dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one was synthesized from2-amino-4,6-dimethoxybenzamide and 4-pyridine carboxaldehyde, using themethod described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.5,7-Dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one (142 mg, 63%) wasisolated as a pale brown solid and then converted to the correspondinghydrochloride (yellow solid). Selected data: MS (m/z): 284.06; MP294-295° C. (hydrochloride).

Example 34

2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one

To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (3.0 g, 20 mmol) inanhydrous THF (100 mL), triphenyl phosphene (10.49 g, 40 mmol),4-(2-hydroxyethyl)morpholine (5.25 g, 40 mmol) andN,N-diisopropylethylamine (7.76 g, 60 mmol) were added. To this stirredsolution was added diethylazodicarboxylate (6.97 g, 40 mmol). Thereaction mixture was stirred at room temperature overnight undernitrogen and diluted with ethyl acetate (200 mL). The organic layer waswashed with water and brine and dried over anhydrous Na₂SO₄. The solventwas removed under reduced pressure. The crude material was purified bycolumn chromatography (silica gel 230-400 mesh; 0-3% methanol in CH₂Cl₂as eluent) to give 3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)benzaldehyde(1.66 g, 32%) as an oil.

To a solution of 2-amino benzamide (136 mg, 1.0 mmol) in N,N-dimethylacetamide (5 mL) were added3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)benzaldehyde (263 mg, 1.0 mmol),sodium hydrogen sulphite (58.5%) (196 mg, 1.1 mmol) andp-toluenesulfonic acid (19 mg, 0.1 mmol). The reaction mixture wasstirred at 150° C. overnight. Water (40 mL) was added. The formed solidwas filtered off, washed with water and a small amount of methanol anddried under vacuum to give the title compound (190 mg, 50%) as anoff-white solid. To a solution of the above compound (174 mg, 0.458mmol) in 2:1 anhydrous CH₂Cl₂-methanol (15 mL) was added 1.0 M solutionof hydrogen chloride in ether (1.5 mL) and the reaction mixture wasstirred at room temperature for 16 h. The solvent was removed underreduced pressure. The residue was triturated with 10% methanol inanhydrous ether to give the hydrochloride of2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one (187mg, 98%), as an off-white solid. Selected data: MS (ES) m/z: 380.10; MP300-302° C. (hydrochloride).

Example 35

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one

A mixture of anthranilamide (0.15 g, 1.10 mmol),4-[2(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde(0.340 g, 1.101 mmol), sodium hydrogensulfite (0.126 g, 1.101 mmol) andp-toluenesulfonic acid (20 mg) in N,N-dimethyl acetamide (5 mL) wasstirred at 150° C. for 3 h under nitrogen. The reaction mixture wascooled to room temperature and diluted with water (20 mL). The solid wascollected by filtration, washed with water (10 mL×3) and dried underhigh vacuum to provide desired compound (328 mg, 70%), as a white solid.A solution of the above described compound (0.316 g, 0.745 mmol) in THF(3 mL) was cooled to 0° C. under nitrogen and TBAF (1.5 mL, 1.49 mmol)was added, followed by stirring at room temperature for 1 h. Thereaction mixture was diluted with cold water (30 mL), the whiteprecipitate was filtered off, washed with water (15 mL×3) and MeOH (20mL×3) and dried under high vacuum, to afford2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (150 mg,65%), as a white solid. Selected data: MS (ES) m/z: 311.04; MP 260-261°C.

Example 36

2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one

2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one wassynthesized from anthranilamide and 4-(pyrimidin-2-yloxy)-benzaldehyde,using the method described for5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one (222 mg,72%) was isolated as a light beige solid. Selected data: MS (m/z):280.98; MP 267-268° C. (decomposed).

Example 37

2-(4-(dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one

2-(4-(Dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-onewas synthesized from 2-amino-4,6-dimethoxybenzamide and4-dimethylamino-1-naphthaldehyde, using the method described for5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(4-(Dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one(75 mg, 26%) was isolated as a yellow solid. Selected data: MS (m/z):376.07; MP 269-271° C.

Example 38

2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide

2-Amino-4,6-dimethoxy-benzamide (150 mg, 0.764 mmol),2-(4-formyl-phenoxy)-acetamide (137 mg, 0.764 mmol), sodium hydrogensulfite (150 mg, 58.5%) and p-toluenesulfonic acid monohydrate (15 mg)in N,N-dimethyl acetamide (15 mL) were heated to 150° C. overnight.N,N-dimethyl acetamide was removed under vacuum and the residue waspoured into water (50 mL). The solid was filtered off and washed withmethanol to yield2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide(74 mg, 27.2%). Selected data: MS (m/z): 356.09; MP 309-311° C. HPLCpurity: 88.57%.

Example 39

2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid

2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid wassynthesized from anthranilamide and 4-formyl phenoxy acetic acid, usingthe method described for5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid (800 mg, 73%)was isolated as a white solid. Selected data: MS (m/z): 296.98; MP285-287° C.

Example 40

2-(4-(dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one

2-(4-(Dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one was synthesizedfrom anthranilamide and 4-dimethylamino-naphthalene-1-carbaldehyde,using the method described for5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(4-(Dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one (240 mg, 69%)was isolated as a pale yellow solid. Selected data: MS (m/z): 316.08; MP224-226° C.

Example 41

2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide

2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide was synthesizedfrom anthranilamide and 2-(4-formyl-phenoxy)-acetamide, using the methoddescribed for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide (183 mg, 56%)was isolated as a light beige solid. Selected data: MS (m/z): 295.97; MP277.5-278.5° C.

Example 42

2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one

2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-onewas synthesized from 2-amino-4,6-dimethoxybenzamide and2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, using the method describedfor 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one(120 mg, 46%) was isolated as a yellow solid. Selected data: MS (m/z):341.03; MP 307.5-309.6° C.

Example 43

5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one

A solution of 4-(4-formyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (1.3 g, 4.47 mmol) in THF (50 mL) was mixed with LAH(0.7 g, 17.87 mmol) and stirred at reflux for 14 h. The reaction wasquenched at room temperature by adding KOH aqueous (14 N, 20 mL). Thesupernatant was decanted and combined with DCM washings, then dilutedwith water (50 mL). The mixture was extracted with DCM (3×50 mL)followed by concentration using a rotary evaporator to give[4-(4-methyl-piperazin-1-yl)-phenyl]-methanol (0.82 g, 89%). To asolution of DMSO (0.56 mL, 7.96 mmol) in DCM (50 mL) at −78° C. wasadded oxalyl chloride (0.7 mL, 7.96 mmol) and the resulting mixture wasstirred at −78° C. for 0.5 h. A solution of[4-(4-methyl-piperazin-1-yl)-phenyl]-methanol (0.82 g, 3.98 mmol) in DCM(20 mL) was slowly added. The reaction was stirred at −78° C. for 1.5 h.Triethylamine (1.7 mL, 11.94 mmol) was added and the reaction wasallowed to gradually warm up to room temperature. After stirring for 4 hthe reaction was quenched by adding sodium bicarbonate aqueous (1 N, 50mL). The mixture was extracted with DCM (3×50 mL) followed byconcentration to afford a residue, which was further purified by columnchromatography to yield 4-(4-methyl-piperazin-1-yl)-benzaldehyde (0.5 g,61%).

5,7-Dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-onewas synthesized from 2-amino-4,6-dimethoxybenzamide and4-(4-methyl-piperazin-1-yl)-benzaldehyde, using the method described for5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one(120 mg, 41%) was converted to the corresponding hydrochloride (a yellowsolid). Selected data: MS (m/z): 381.11; MP 252.4-254.2° C.(di-hydrochloride).

Example 44

2-(4-(dimethylamino)pyridin-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one

A solution of 4,5-dimethoxy-2-nitrobenzamide (10 g, 44.24 mmol) in MeOH(260 mL) was mixed with palladium/carbon (2 g) and subjected tohydrogenation (50 psi) for 20 h. The reaction mixture was filteredthrough a Celite pad, concentrated to yield 8.7 g of2-amino-4,5-dimethoxybenzamide (100%).

2-(4-(Dimethylamino)naphthalen-1-yl)-6,7-dimethoxyquinazolin-4(3H)-onewas synthesized from 2-amino-4,5-dimethoxy-benzamide and4-Dimethylamino-naphthalene-1-carbaldehyde, using the method describedfor 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(4-(dimethylamino)naphthalen-1-yl)-6,7-dimethoxy-quinazolin-4(3H)-one(159 mg, 56%) was isolated as a white solid. Selected data: MS (m/z):376.13; MP 235.5-236.5° C.

Example 45

2-(4-(bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one

2-(4-(Bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one wassynthesized from anthranilamide and4-[bis-(2-hydroxy-ethyl)-amino]-benzaldehyde, using the method describedfor 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(4-(Bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one (150 mg, 42%)was isolated as a brown solid. Selected data: MS (m/z): 326.03; MP228-230° C.

Example 46

2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-onewas synthesized from 2-amino-4,6-dimethoxybenzamide and4-[bis-(2-hydroxy-ethyl)-amino]-benzaldehyde, using the method describedfor 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-quinazolin-4(3H)-one(120 mg, 41%) was isolated as a yellow solid. Selected data: MS (m/z):386.15; MP 249-251° C.

Example 47

2-(4-bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one

2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-onewas synthesized from 2-amino-4,5-dimethoxy-benzamide and4-(N,N-bis(2-hydroxyethyl)amino)benzaldehyde, using the method describedfor 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one(72 mg, 24%) was isolated as a yellow solid. Selected data: MS (m/z):386.15; MP 268-270° C.

Example 48

2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one

2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-onewas synthesized from 2-amino-4,5-dimethoxybenzamide and2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, using the method describedfor 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxy-quinazolin-4(3H)-one(180 mg, 69%) was isolated as a light yellow solid. Selected data: MS(m/z): 341.03; MP 316.4-318.2° C.

Example 49

5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one

A solution of 4-iodobenzaldehyde (1 g, 4.31 mmol) in MeOH (50 mL) wasmixed with trimethyl orthoformate (4 mL, 36.10 mmol) andp-toluenesulfonic acid (5 mg). The reaction was stirred at roomtemperature for 3 h and then quenched by adding excess of sodiumbicarbonate solid and stirred for 1 h. The solid was removed byfiltration and the filtrate was concentrated to yield1-dimethoxymethyl-4-iodo-benzene (1.2 g, 100%). A mixture of1-dimethoxymethyl-4-iodo-benzene (1.2 g, 4.31 mmol), cesium carbonate(1.4 g, 4.31 mmol), morpholine (0.375 g, 4.31 mmol), and palladiumtetrakis(triphenyl) phosphine (0.25 g, 0.216 mmol) in toluene (60 mL)and tert-butanol (10 mL) was thoroughly degassed and stirred at 110° C.for 28 h. The reaction was quenched by adding water (50 mL), extractedwith DCM (3×100 mL), concentrated to afford a solid residue.Purification by column chromatography left4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 60%). A solution of4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 2.58 mmol) in THF (20mL) was mixed with HCl in ether (10 mL, 10 mmol) and stirred at roomtemperature for 2 h. The reaction mixture was then neutralized with 1 Nsodium bicarbonate aqueous to pH 9 and extracted with DCM (3×100 mL), toafford 4-morpholin-4-yl-benzaldehyde (0.37 g, 75%).

A mixture of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.765 mmol),4-morpholin-4-yl-benzaldehyde (0.15 g, 0.765 mmol), sodiumhydrogensulfite (0.136 g, 0.765 mmol) and p-toluenesulfonic acid (10 mg)in N,N-dimethyl acetamide (10 mL) was stirred at 155° C. for 14 h. Thereaction mixture was cooled to room temperature and diluted with water(50 mL). The solid was collected by filtration, washed with water andMeOH to yield 5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one(0.109 g, 39%).

A solution of 5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one(0.109 g, 0.297 mmol) in DCM (5 mL) and MeOH (5 mL) was mixed with HClin ether (3 mL, 3 mmol), stirred for 1.5 h, concentrated. The solidformed was rinsed with Hexanes, collected by filtration and washed withhexanes and DCM to yield the hydrochloride (0.115 g, 95%) as a brownsolid. Selected data: MS (m/z): 368.13; MP 217.5-219.4° C.(hydrochloride).

Example 50

7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one

Malonic acid (41.62 g, 0.4 mol), 2,4,6-trichlorophenol (157.96 g, 0.8mol) and POCl₃ (134.9 g, 80.6 mL) were mixed in a flask and stirredunder reflux overnight. The reaction mixture was cooled to 70° C. andpoured into ice-water. The solid was filtered off, washed with water anddried (183.73 g, quantitative). The compound from above (183.73 g, 0.4mol), ethyl 3-aminocrotonate (51.7 g, 0.4 mol) and bromobenzene (200 mL)were mixed. The reaction mixture was heated to reflux for 4 h and thenstirred at room temperature overnight, diluted with ethyl acetate andfiltered off. The solid was washed with ethyl acetate to obtain alight-yellow solid (107.7 g). The solid from above (107.7 g, 0.4 mol)was dissolved in POCl₃ (300 mL, 2.5 mol) and the reaction mixture wasrefluxed for 2 h. POCl₃ was removed and the residue was poured intowater, and extracted with DCM. The solvent was removed to obtain a crudecompound (73.02 g) which was used for the next step without furtherpurification. The compound (73.02 g, 0.31 mol) was dissolved in methanoland sodium methoxide solution in methanol (25%) was added and themixture was refluxed overnight (˜14 h). The reaction mixture wasquenched with acetic acid. DCM was added and the solvent was evaporatedto leave a crude product (64.43 g), which was used for the next stepwithout further purification. The compound (64.0 g) was dissolved in amixture of methanol and THF. To this mixture was added lithium hydroxide(63.7 g, 1.52 mol) in water. The reaction mixture was refluxed for 3 d.The solvent was removed and conc. HCl (160 mL) was added and the mixturewas concentrated. The residue was freeze dried. The crude salt (69.1 g)was used for the next step without further purification. The salt (34.6g, 0.148 mol) was dissolved in DCM and oxalyl chloride (37.6 g, 25.8 mL)was added, followed by DMF (0.5 mL). The reaction mixture was stirredunder nitrogen overnight. The solvent was evaporated in vacuo to obtainthe crude acid chloride, which was used for the next step withoutfurther purification. The acid chloride was dissolved in DCM and ammoniagas was passed through the solution for 30 min. The reaction mixture wasstirred overnight. Water was added and the solid was filtered off andwashed with DCM. A small portion of pure A-ring building block (5 g) wasisolated and crude materials (20 g) were saved.

To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (5.04 g, 34.3 mmol)and PPh₃ (18.1 g, 68.6 mmol) in anhydrous THF (200 mL), were added4-(2-hydroxyethyl)-morpholine (9.01 g, 68.6 mmol) andisopropylethylamine. To this stirred solution was added DEAD (11.95 g,68.6 mmol) and the reaction mixture was stirred at room temperatureovernight. THF was removed and ethyl acetate was added. The mixture waswashed with water and brine. The crude was dissolved in DCM and washedwith 1 N HCl. The aqueous layer was basified with 5% NaOH and saturatedNaHCO₃ solution. The mixture was extracted with ethyl acetate andconcentrated. The crude was dissolved in ether and hydrogen chloride inether was added. The solvent was decanted off, dissolved in water,basified with solid NaHCO₃ and NaHCO₃ solution, extracted with ethylacetate, and concentrated. The crude was purified by silica gel (100 g)column chromatography, employing 30-50% ethyl acetate in hexane aseluents to give the desired B-ring building block (0.455 g).

The A-ring building block (0.344 g, 1.75 mmol) was dissolved inanhydrous THF (50 mL) and cooled to −78° C. n-Butyllithium (3.3 mL, 5.25mmol of 1.6 M in hexane) was added drop-wise and the temperature wasincreased to −20° C. for 40 min, to −10° C. for 1 h, and to −5 to −2° C.for 40 min, before the reaction mixture was cooled again to −78° C. andthe B-ring building block (0.455 g, 1.75 mmol) in acetonitrile (10 mL)was added quickly. The reaction mixture was stirred at room temperatureovernight (˜20 h). The dark brown solution was quenched with acetic acidand refluxed for 1 h. Water was added and extracted with DCM. The crudewas purified by silica gel (50 g) column chromatography, using hexane(500 mL), hexane:ethyl acetate (1:1, 750 mL), and then hexane:ethylacetate:methanol (3:2:1) as eluents, to give7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one(100 mg, 13%) as an off-white solid. Selected data: MS (m/z): 440.28; MP212.5-212.9° C.

Example 51

3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one

Methyl acetoacetate (69.67 g, 0.6 mol) in dry THF (350 mL) was cooled to−5° C. and sodium hydride in mineral oil (24.5 g, 60%) was added at −5to 0° C. over 30 min. Diketene (50.4 g) in dry THF (80 mL) was addeddrop-wise at 5° C. over 20 min. The resulting solution was allowed tostir for 1.0 h at −5° C., after which it was allowed to warm to roomtemperature and stir overnight. Acetic acid (35 mL) was added and theTHF solvent was removed. Water (200 mL) and ethyl acetate (300 mL) wereadded to the residue and the pH was adjusted to 5.0 by addition of HClsolution. The organic layer was separated and washed with brine anddried over sodium sulfate. After column purification andrecrystalization, compound A (26.6 g, 24.3%) was obtained.

Sodium hydride in mineral oil (11.2 g, 0.279 mol, 60%) was added tocompound A (24.8 g, 0.136 mol) in DMF (150 mL). The reaction was cooledto −30° C. and methyl iodide (21.3 mL, 0.341 mol) was added and thereaction was kept at room temperature overnight. Sodium iodide wasfiltered off and DMF was removed. The residue was mixed with water (100mL) and extracted with ethyl acetate. The organic layer was washed withbrine and dried over sodium sulfate. The crude mixture was purified bycolumn chromatography to yield compound B (11.40 g, 39.9%). To asolution of compound B (11.4 g, 0.054 mole) in dry CCl₄ (90 mL) wasadded N-bromosuccinimide (10.6 g, 0.0596 mol). The mixture was refluxedovernight and CCl₄ solvent was removed. Water (100 mL) was added to theresidue. After stirring for a while the solid was filtered off andwashed with water, ethyl acetate (10 mL) and hexane (30 mL) to yieldcompound (13.1 g, 83.9%). Compound C (12.5 g, 0.043 mol), chloromethylmethyl ether (81.0 g) and anhydrous zinc chloride (7.0 g, 0.051 mol)were kept at room temperature overnight. Chloromethyl methyl ether wasremoved and the residue was mixed with water and the pH was adjusted to7.0 using sodium bicarbonate. The mixture was extracted with ethylacetate. The organic layer was washed with brine and dried over sodiumsulfate. Compound D (7.39 g, 50.6%) was obtained after columnchromatography. A solution of compound D (7.39 g, 0.022 mol), morpholine(7.62 g, 0.088 mol) and anhydrous THF (20 mL) was kept at roomtemperature overnight. The solvent was evaporated. Water and ethylacetate were added to the residue, and pH was adjusted to 9.0 withsodium bicarbonate. The organic layer was washed with brine and driedover sodium sulfate, and concentrated. Compound E (5.4 g, 63.8%) wasobtained after column chromatography. The hydrogenation reaction wascarried out at 50 psi with compound E (5.4 g, 0.014 mol) in THF (100 mL)and triethyl amine (3.9 mL) with 10% Pd/C (2.6 g) as a catalyst for 2 d.After the catalyst was filtered off, the organic layer was purified bycolumn chromatography to yield product F (3.20 g, 74.4%). Compound F(3.20 g, 0.0103 mol) was dissolved in ethanol (30 mL) and potassiumhydroxide (2.31 g, 0.041 mol) in water (20 mL) was added and thereaction mixture was heated to 100° C. overnight. The solvent wasremoved, pH was adjusted to 6.0 and the water was removed. The residuewas further dried under high vacuum and the compound was extracted withethanol to yield compound G (2.95 g, 99%). Compound G (1.80 g, 6.1 mmol)with thionyl chloride (3 mL, 0.0411 mol) was refluxed for 1 h before theexcess thionyl chloride was removed and the residue was dried under highvacuum. Anhydrous THF (20 mL) was added and ammonia gas was bubbled intothe reaction mixture for 2 h. THF was removed and pH was adjusted to8.0-9.0. The mixture was extracted with dichloromethane and dried oversodium sulfate to give compound H (1.30 g, 72.4%).

NaH in mineral oil (1.14 g, 0.0285 mol, 60%) was added to4-hydroxy-3,5-dimethylbenzonitrile (4.0 g, 0.027 mol) in anhydrous DMF(20 mL) followed by benzyl bromide (3.27 mL, 0.027 mol). The reactionwas kept at room temperature overnight. The reaction mixture was pouredinto water and the solid was filtered off and washed with hexane toyield Compound I (5.7 g, 89%). Compound I was used for the next stepreaction without further purification. BuLi (1.60 M, 10.2 mL) was addeddrop-wise to compound H (0.8 g, 2.72 mmol) in anhydrous THF (25 mL) at−10° C. The reaction mixture was kept at 0° C. for one h before thecooling bath was removed. The reaction mixture was stirred for 45minutes. Compound I (0.65 g, 2.72 mmol) in anhydrous THF (5 mL) wasadded drop-wise at −10° C. and the reaction was continued for a further45 min. Water (20 mL) was added. The mixture was extracted with ethylacetate. The solvent was removed and the residue was purified by columnchromatography to yield compound J (0.180 g, 12.8%). Compound J (180 mg)in methanol (80 mL) was hydrogenated at 50 psi for 3 h, using 10% Pd/Cas the catalyst. The catalyst and solvent were removed and the residuewas purified by column chromatography to yield3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one(28 mg, 18.8%) as a white solid. Selected data: MS (m/z): 424.21; MP158-161° C.

Example 52

2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one

To a solution of 2-amino-4,5-dimethoxybenzamide (0.157 g, 0.8 mmol) inN,N-dimethylacetamide (5 mL) were added3,5-dimethyl-4-hydroxybenzaldehyde (0.120 g, 0.8 mmol), sodium hydrogensulphite (58.5%, 0.156 g, 0.88 mmol) and p-toluenesulfonic acid (15 mg,0.08 mmol). The reaction mixture was stirred at 150° C. for 3 h. Thereaction mixture was cooled to room temperature and water (40 mL) wasadded. A white precipitate was formed and filtered off, washed withwater and a small amount of methanol and dried under vacuum to give2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one(0.230 g, 88% yield) as an off-white solid. Selected data: MS (ES) m/z:327.12; MP>300° C.

Example 53

3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoicacid

To a solution of 4-iodobenzaldehyde (0.116 g, 0.5 mmol), acroleindiethylacetal (0.3 mL, 1.5 mmol), tetra-n-butylammonium chloride (0.139g, 0.5 mmol) and triethylamine in anhydrous dimethylformamide (2 mL),palladium acetate (0.003 g, 0.015 mmol) was added. The reaction mixturewas heated at 90° C. and stirred for 16 h. The reaction mixture wasdiluted with 2 N hydrochloric acid and extracted with diethyl ether. Thesolvent was evaporated in vacuo to leave a residue which was purified bycolumn chromatography (silica gel) employing 1-5% ethyl acetate inhexane as eluents to obtain 3-(4-formyl-phenyl)-propionic acid ethylester (0.734 g).

To a round-bottomed flask were added 2-amino-4,6-dimethoxy-benzamide(0.161 g, 0.82 mmol), 3-(4-formyl-phenyl)-propionic acid ethyl ester(0.170 g, 0.82 mmol), sodium bisulfite (0.160 g, 0.902 mmol),p-toluenesulfonic acid (0.016 g, 0.082 mmol) and N,N-dimethylacetamide(10 mL). The reaction mixture was refluxed at 155° C. for 16 h beforebeing cooled to room temperature. Water was added and the precipitatedsolid was filtered off and washed with water and methanol to obtain3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionicacid ethyl ester (0.304 g, 97%). The compound3-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenyl]-propionicacid ethyl ester (0.304 g, 0.795 mmol) was taken up in a 1:1 mixture ofTHF and methanol (6 mL). A solution of potassium hydroxide (0.089 g,1.59 mmol) in water (6 mL) was added to the reaction mixture and stirredat room temperature for 16 h. The solvent was removed and the reactionmixture was acidified with 1 N hydrochloric acid. The precipitated solidwas filtered off and washed with water and methanol. The solid wasfurther washed with methanol to obtain3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoicacid (0.143 g, 51%). Selected data: MS (ES) m/z: 355.0; MP 250.6-251.1°C.

Example 54

N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide

To a round-bottomed flask were added 2-amino-5-nitro-benzamide (0.681 g,3.76 mmol), 4-hydroxy-3,5-dimethyl-benzaldehyde (0.565 g, 3.76 mmol),sodium bisulfite (0.747 g, 4.2 mmol), p-toluenesulfonic acid,monohydrate (0.072 g, 0.376 mmol) and N,N-dimethylacetamide (60 mL). Thereaction mixture was refluxed at 155° C. for 16 h before being cooled toroom temperature. Water was added and the precipitated solid wasfiltered off, washed with water and methanol to obtain a crude which waspurified by column chromatography (silica gel (50 g) employing 1-20%methanol in dichloromethane as eluents, to obtain2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g,19%). The compound2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g,0.71 mmol) was hydrogenated in dimethyl formamide (20 mL) usingpalladium on activated carbon (0.076 g, 0.071 mmol) at room temperaturefor 14 h. The solvent was evaporated and the crude was purified bycolumn chromatography (silica gel 25 g) employing 1-5% methanol indichloromethane as eluents to obtain6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.132 g).The compound6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one wasdissolved in pyridine under nitrogen. Acetic anhydride was added at roomtemperature and stirred for 4 h. Pyridine was removed and the residuewas dried. Methanol was added to the flask and a solution of potassiumcarbonate in water was added and stirred for 4 h. The solvent wasremoved, acidified with 1 N hydrochloric acid and the precipitated solidwas filtered off and dried to obtainN-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide(0.037 g, 17%). Selected data: MS (ES) m/z: 324.1; MP 336.5° C.(decomposed).

Example 55

2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide

A solution of 4-hydroxy-3,5-dimethoxybenzaldehyde (1.0 g, 6.66 mmol) inDMF (10 mL) was cooled to 0° C. under nitrogen. NaH (0.4 g, 10 mmol, 60%in oil) was added portion-wise. The reaction was stirred for 30 min;then 2-bromoacetamide (0.918 g, 6.66 mmol) was added and stirring wascontinued for 36 h at room temperature. The DMF was removed underreduced pressure and water (50 mL) was added. The mixture was extractedwith EtOAc (50 mL×3). The combined organic layers were washed with anaqueous solution of NaOH (50 mL, 10%), washed with water (50 mL) andbrine solution (50 mL) and dried over MgSO₄ and concentrated to give 0.6g of crude intermediate, which was purified by flash columnchromatography to provide the desired intermediate (366 mg, 26%), as awhite solid. A mixture of 2-amino-4,5-dimethoxybenzamide (0.2 g, 1.019mmol), 2-(4-formyl-2,6-dimethyl-phenoxy acetamide (0.211 g, 1.019 mmol),sodium hydrogensulfite (0.116 g, 1.121 mmol) and p-toluenesulfonic acid(20 mg) in N,N-dimethyl acetamide (5 mL) was stirred at 150° C. for 16 hunder nitrogen. The reaction mixture was cooled to room temperature andwater (50 mL) was added. The white precipitate was filtered off andwashed with cold water (30 mL×2) and dried under high vacuum to provide2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide(300 mg, 76%) as a off white solid. Selected data: MS (ES) m/z: 384.1(M+1); MP 354-356° C.

Example 56

2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A mixture of 3-chloro-4-hydroxy-benzaldehyde (227 mg, 1.45 mmol),(2-bromoethoxy)-tert-butyldimethylsilane (347 mg, 1.45 mmol), cesiumcarbonate (709 mg, 2.18 mmol) and DMSO (2 mL) was stirred at 80° C. for17 h. The reaction mixture was cooled to room temperature and water (50mL) was added. The resulting precipitate was filtered off, washed withwater, air-dried, dissolved in a small amount of ethyl acetate andpurified by column chromatography.4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chlorobenzaldehyde wasobtained as a white solid (yield: 267 mg, 58%). To a 100 mLround-bottomed flask was added 2-amino-4,6-dimethoxy-benzamide (166 mg,0.85 mmol),4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-benzaldehyde (267mg, 0.85 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol),sodium hydrogensulfite (216 mg, 1.2 mmol) and dimethylacetamide (5 mL).The mixture was stirred in a 150° C. oil bath under nitrogen for 17 h.After cooling to room temperature, water (50 mL) was added. Theprecipitate was filtered off, washed with water and air-dried. The crudeproduct was purified by column chromatography to give2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(45 mg, 23%). Selected data: MS (ES) m/z: 377.03; MP 287-288° C.(decomposed).

Example 57

2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

NaH (0.12 g, 0.0050 mol, 60% in mineral oil) was added to4-hydroxy-3-methoxylbenzalde (0.636 g, 4.18 mmol) in anhydrous DMF (15mL) and then (2-bromoethoxy)-tert-butyl-dimethylsilane (1.0 g, 4.18mmol) was added and the reaction was kept at room temperature overnight.The reaction mixture was poured into water. The mixture was extractedwith dichloromethane and the combined organic layers were passed througha column to yield4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-methoxybenzaldehyde (170mg, 13%). 2-Amino-4,6-dimethoxy-benzamide (101 mg, 0.515 mmol),4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-methoxybenzaldehyde (160mg, 0.515 mmol), sodium hydrogen sulfite (100 mg, 58.5%) andp-toluenesulfonic acid monohydrate (10 mg) were mixed with N,N-dimethylacetamide (15 mL) and heated to 150° C. for 16 h. N,N-dimethyl acetamidewas removed under vacuum and the residue was poured into water (50 mL).The solid was filtered off and further purified by column chromatographyto yield2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(15 mg, 7.8%). Selected data: MS (ES) m/z: 373.1; MP 246-248° C.

Example 58

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one

To a solution of 2-amino-5,6-dimethoxy-benzamide (200 mg, 1.01 mmol) and4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (314mg, 1.01 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO₃(199 mg, 1.12mmol) and p-TSA (19 mg, 0.1 mmol) were added and the reaction mixturewas heated at 150° C. for 3 h, cooled to room temperature and pouredinto water. The solid was collected and washed with methanol to give 280mg of mixture products. To a solution of the above mixture (280 mg,0.578 mmol) in THF (20 mL), TBAF (150 mg, 0.578 mmol) was added at 0° C.and allowed to stir at room temperature for 3 h. The reaction mixturewas quenched by addition of water. The organic layer was separated andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water, brine and dried over Na₂SO₄. The solventwas removed to give crude product. The crude product was purified bycolumn chromatography (silica gel 230-400 mesh; 2% methanol in CH₂Cl₂ aseluent) to give2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one(135 mg, 63%). Selected data: MS (ES) m/z: 371.1; MP>300° C.

Example 59

5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one

To a solution of 4-bromomethyl-benzoic acid ethyl ester (4.0 g, 16.46mmol) in THF (30 mL), N-methyl piperazine (3.29 g, 32.92 mmol) was addedand the reaction mixture was stirred for 48 h at room temperature. Then,the reaction mixture was diluted with water and the mixture wasextracted with ethyl acetate. The combined organic layers were washedwell with water, brine, and dried over Na₂SO₄. The solvent was removedto give 4.0 g of crude product in 93% yield. Lithium aluminum hydride(0.771 g, 20.32 mmol) was taken in a 3-neck dry flask and THF was addedon cooling. A solution of 4-(4-methyl piperazin-1-ylmethyl)-benzoic acidethyl ester (4.0 g, 15.26 mmol) in THF (10 mL) was added slowly oncooling. After completion of addition, the reaction mixture was heatedat reflux for 3 h. The reaction mixture was cooled to 0° C. and 10% NaOHsolution was added, followed by water. The organic layer was separatedand the aqueous layer was extracted with ethyl acetate. The combinedorganic layer was washed well with water, brine and dried over Na₂SO₄.The solvent was removed to give 2.4 g of crude product in 67% yield.

A 3-neck flask with anhydrous CH₂Cl₂ (100 mL) was cooled to the −78° C.Then, oxalyl chloride (1.66 g, 13.09 mmol) and DMSO (1.7 g, 21.8 mmol)were added at −78° C. and stirred for 15 min at −78° C. The solution of(4-(4-methyl piperazin-1-ylmethyl)phenyl)-methanol (2.4 g, 10.9 mmol) inCH₂Cl₂ (10 mL) was added at −78° C. and stirred at −78° C. for 1 h. ThenEt₃N (4.41 g, 43.63 mmol) was added at −78° C. The reaction mixture wasallowed to come to room temperature. Water was added and the organiclayer was separated. The aqueous layer was extracted with CH₂Cl₂. Thecombined organic layer was washed with water, brine and dried overNa₂SO₄. Then, solvent was removed to give 2.23 g of crude product in 94%yield.

To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and4-(4-methyl piperazin-1-ylmethyl)benzaldehyde (166 mg, 0.76 mmol) inN,N-dimethyl acetamide (10 mL), NaHSO₃ (149 mg, 0.84 mmol) and p-TSA(319 mg, 1.68 mmol) were added and the reaction mixture was heated at150° C. for 3 h. The mixture was cooled to room temperature and waterwas added and neutralized by addition of NaHCO₃. The solvent was removedunder reduced pressure to give the crude product. The crude was purifiedby column chromatography (silica gel 230-400 mesh; 4% NH₃ inmethanol/CH₂Cl₂ as eluent) to give the product5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-oneas a free base, which was converted to the hydrochloride salt (115 mg,35%). Selected data: MS (ES) m/z: 395.2; MP 275-277° C. (hydrochloride).

Example 60

N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide

A mixture of 2,6-dimethyl-phenylamine (0.62 mL, 5.0 mmol), DMSO (100mL), conc. Aqueous HCl (36.5-38%, 5.0 mL), and dried CuCl₂ was stirredat 90° C. under nitrogen for 5 h. The reaction was quenched with water.The pH of the mixture was adjusted to ˜8 using a 10% sodium hydroxidesolution. The mixture was extracted with ether (3×100 mL). The solutionwas dried over Na₂SO₄ and concentrated to dryness. The resulting brownoil was dissolved in dichloromethane (anhydrous, 20 mL) andN-ethyldiisopropylamine (DIPEA, 1.0 mL, 5.8 mmol) was added. The mixturewas cooled to 0° C., acetoxyacetyl chloride (0.8 mL, 7.4 mmol) was addedslowly. The mixture was stirred at room temperature under nitrogen for17 h. The mixture was concentrated to dryness and purified by columnchromatography. Acetic acid(4-formyl-2,6-dimethyl-phenylcarbamoyl)-methyl ester was obtained asyellow/beige solid (96 mg). A mixture of acetic acid(4-formyl-2,6-dimethyl-phenylcarbamoyl)-methyl ester (96 mg, 0.38 mmol),2-amino-4,6-dimethoxy-benzamide (74 mg, 0.38 mmol), p-toluenesulfonicacid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (96 mg, 0.53mmol) and dimethylacetamide (3 mL) was stirred in a 150° C. oil bathunder nitrogen for 17 h. After cooling to room temperature, water (50mL) was added. The precipitate was filtered off and washed with water.The filtrate was extracted with dichloromethane, dried over Na₂SO₄,purified by column chromatography, using (1) 5%methanol/dichloromethane, and (2) 10% methanol/dichloromethane aseluents. Acetic acid[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenylcarbamoyl]-methylester was obtained as a beige solid (70 mg, 43%). Acetic acid[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenylcarbamoyl]-methylester (70 mg, 0.16 mmol) was dissolved in methanol/dichloromethane (10mL) and a solution of potassium carbonate (442 mg, 20 mmol) in water wasadded. The solution was stirred at room temperature for 17 h. 2 N HClwas added to adjust the reaction mixture pH to ˜8. The mixture was thenconcentrated under reduced pressure. The resulting precipitate wasfiltered off, washed with water, air-dried, then washed with ether anddried, leavingN-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide(30 mg, 49%) as a light brown solid. Selected data: MS (ES) m/z: 384.1;MP 190-192° C.

Example 61

7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one

2-[4-(5-amino-2,4-dimethoxy-[1,6]naphthyridin-7-yl)-2,6-dimethyl-phenoxyl]-ethanol(0.302 g, 0.82 mmol) in water (5 mL) and conc. Hydrochloric acid (3 mL)were mixed with stirring. The reaction mixture was cooled to 0° C. and asolution of sodium nitrite (0.305 g, 4.42 mmol) in water (3 mL) wasadded dropwise. The reaction mixture was stirred at 0° C. for 40 min. Tothe reaction mixture was added 1 N hydrochloric acid (10 mL) and heatedat 55° C. for 50 min and then stirred at room temperature overnight. Thereaction mixture was extracted with dichloromethane and the aqueouslayer was basified with aqueous 5% NaOH and saturated NaHCO₃ solution.Water was evaporated and the organic compound was washed with adichloromethane/methanol solution and concentrated to leave a crudewhich was purified by silica gel (50 g) column chromatography, employing50% ethyl acetate in hexane and hexane/ethyl acetate/methanol (3:2:1) aseluent, to obtain7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one(0.080 g, 26%). Selected data: MS (ES) m/z: 371.1; MP 224.9-225.4° C.

Example 62

2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one

2-Amino-5-morpholino-4-ylmethyl-benzamide hydrochloride salt (200 mg,0.649 mmol), 4-hydroxy-3,5-dimethylbenzalde (97.4 mg, 0.649 mmol),sodium hydrogen sulfite (127 mg, 58.5%), and p-toluenesulfonic acidmonohydrate (10 mg) in N,N-dimethyl acetamide (10 mL) were heated to150° C. for 6 h. N,N-dimethyl acetamide was removed under vacuum. Theresidue was poured into water (50 mL) and dichloromethane was used toextract the compound, which was further purified by columnchromatography to yield 30 mg free base of2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one.The base was treated with 1.0 M HCl to give the correspondinghydrochloride (36 mg, 11.68%). Selected data: MS (ES) m/z: 366.1; mp284-286° C. (hydrochloride).

Example 63

2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one

To a solution of 4,6-dimethoxy-2-methyl nicotinamide (2.0 g, 10.2 mmol)in THF (80 mL), n-butyl lithium (19.12 mL, 30.6 mmol, 1.6 M solution inhexane) was added slowly under nitrogen at −78° C. After completion ofaddition the mixture was stirred for 1 h at 0° C. Then cooled to −78° C.and a solution of 4-methoxy benzonitrile (1.65 g, 10.2 mmol) in THF (10mL) was added quickly. The cooling bath was removed and the reactionmixture was allowed to warm to room temperature and stirred for 16 h atroom temperature. Saturated NH₄Cl solution was added with cooling. Theorganic layer was washed with water, brine, dried over Na₂SO₄ andconcentrated to give crude product. The crude product was purified bychromatography using 50% ethyl acetate in hexane and then 2% methanol inethyl acetate to give2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one(410 mg, 12%), as a yellow solid. Selected data: MS (ES) m/z: 341.1; mp262-263° C. (at decomposition).

Example 64

2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl2,6-dimethylphenoxy)acetic acid

A solution of sodium hydroxide (2.53 g, 63.25 mmol) in water (65 mL) wasadded to a mixture of bromoacetic acid (5.27 g, 37.95 mmol) and3,5-dimethyl-4-hydroxy-benzaldehyde (1.9 g, 12.65 mmol) in water (30mL). The reaction mixture was stirred at 100° C. for 24 h. The solutionwas acidified to pH ˜2 with conc. HCl. The brown solid was filtered off,washed with water, dried under vacuum, and purified by columnchromatography to give (4-formyl-2,6-dimethyl-phenoxy)-acetic acid as alight brown solid (0.40 g). To a solution of2-amino-4,6-dimethoxybenzamide (0.150 g, 0.764 mmol) in N,N-dimethylacetamide (5 mL) were added (4-formyl-2,6-dimethyl-phenoxy)-acetic acid(0.159 g, 0.764 mmol), sodium hydrogen sulphite (58.5%, 0.150 g, 0.84mmol) and p-toluenesulfonic acid (15 mg, 0.0764 mmol). The reactionmixture was stirred at 150° C. for 3 h. it was then cooled to roomtemperature and water (40 mL) was added. A yellow precipitate was formedand filtered off, washed with water and a small amount of methanol.Triturated with 10% methanol in ether to give 0.084 g of compound, whichwas further purified by preparative HPLC to give2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)aceticacid (47 mg, 13%) as a white solid. Selected data: MS (ES) m/z: 384.0;MP 270-272° C.

Example 65

N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide

To a solution of 4-aminobenzaldehyde (1 g, 8.52 mmol) at 0° C. undernitrogen atmosphere were added triethylamine (2.3 mL, 16.5 mmol),4-dimethylaminopyridine (0.1 g, 0.82 mmol) and acetoxyacetyl chloride(1.77 mL, 16.5 mmol). The reaction mixture was allowed to warm up toroom temperature and was stirred for 2.5 h. Triethylamine (1.15 mL, 8.25mmol) and acetoxyacetyl chloride (0.88 mL, 8.25 mmol) were added and thereaction mixture was stirred for 1 h more. The reaction mixture waspoured into a 1 M hydrochloric acid solution (60 mL), then extractedwith methylene chloride (20 mL×3) and the combined organic layers werewashed with saturated aqueous sodium bicarbonate solution and dried overanhydrous sodium sulfate. The crude solid (3.17 g) was purified by flashcolumn chromatography to provide pure acetic acid(4-formyl-phenylcarbamoyl)-methyl ester (1.14 g, 62% yield) as an orangesolid. A mixture of 2-amino-4,6-dimethoxy-benzamide (0.15 g, 0.76 mmol),Acetic acid (4-formyl-phenylcarbamoyl)-methyl ester (0.169 g, 0.76mmol), sodium hydrogensulfite (0.087 g, 0.84 mmol) and p-toluenesulfonicacid (15 mg, 0.076 mmol) in N,N-dimethyl acetamide (5 mL) was stirred at150° C. for 4.5 h under nitrogen. The reaction mixture was cooled toroom temperature and diluted with cold water (60 mL) to obtain a yellowsolid. The yellow solid was filtered off, washed with cold water (20mL×2), methanol and dried under vacuum to provide crude compound (230mg, 75%).

The yellow solid was triturated with ether and methanol to provideacetic acid[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenylcarbamoyl]-methylester (112 mg, 37%). To a solution of acetic acid[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-phenylcarbamoyl]-methylester (0.23 g, 0.59 mmol) in THF/methanol mixture (3.5 mL/3.5 mL) wasadded potassium carbonate (0.41 g, 2.95 mmol). The reaction mixture washeated at reflux overnight and the solvent was concentrated under vacuumand diluted with water (60 mL) to obtain a precipitate. The yellow solidwas filtered, washed with water (20 mL), methanol and dried under vacuumto provide crude compound. The yellow solid was triturated with etherand methanol to provide the desired compoundN-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide(55 mg, 55%). Selected data: MS (ES) m/z: 356.1; mp 318-319° C.

Example 66

5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one

To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46mmol) in THF (30 mL), morpholine (2.87 g, 32.92 mmol) was added and thereaction mixture was stirred for 48 h at room temperature. The reactionmixture was diluted with water and the product was extracted with ethylacetate. The combined organic layers were washed with water, brine, anddried over Na₂SO₄. The solvent was removed to give 3.4 g of crudeproduct in 83% yield.

LAH (0.571 g, 15.05 mmol) was added to a 3-neck dry flask and THF (50mL) was added on cooling. A solution of 4-morpholin-4-ylmethyl)-benzoicacid ethyl ester (3.0 g, 12.04 mmol) in THF (10 mL) was added slowly oncooling. After completion of addition, the reaction mixture was heatedat reflux for 3 h. The reaction mixture was cooled to 0° C. and a 10%NaOH solution was added carefully followed by water. The organic layerwas separated and the aqueous layer was extracted with ethyl acetate.The combined organic layers were washed with water, brine and dried overNa₂SO₄. The solvent was removed to give (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 80%). To the 3-flask anhydrous CH₂Cl₂ (100 mL) wasadded and cooled to −78° C. Oxalyl chloride (1.47 g, 11.59 mmol) andDMSO (1.5 g, 19.32 mmol) were added at −78° C. The reaction mixture wasstirred for 15 min at −78° C. A solution of (4-morpholin-4-ylmethylphenyl) methanol (2.0 g, 9.66 mmol) in CH₂Cl₂ (10 mL) was added at −78°C. and the mixture was stirred at −78° C. for 1 h. Then, Et₃N (3.9 g,38.64 mmol) was added. The reaction mixture was allowed to come at roomtemperature. Water was added and the organic layer was isolated. Theaqueous layer was extracted with CH₂Cl₂. The combined organic layerswere washed with water, brine and dried over Na₂SO₄. Then solvent wasremoved to give crude 4-morpholin-4-ylmethyl benzaldehyde (1.6 g, 81%).

To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and4-morpholin-4-ylmethyl benzaldehyde (156 mg, 0.76 mmol) in N,N-dimethylacetamide (10 mL), NaHSO₃ (150 mg, 0.84 mmol) and p-TSA (174 mg, 0.91mmol) were added and the reaction mixture was heated at 150° C. for 5 h.The reaction mixture was cooled to room temperature, water was added andthe mixture was neutralized with NaHCO₃. The solvent was removed underreduced pressure to give the crude product, which was purified by columnchromatography to give5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one, whichwas converted to the hydrochloride salt (165 mg, 51%). Selected data: MS(ES) m/z: 382.07; MP 206-208° C. (at decomposition).

Example 67

2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46mmol) in THF (30 mL), N-ethyl piperazine (3.76 g, 32.92 mmol) was addedand the reaction mixture was stirred for 16 h at room temperature. Thereaction mixture was diluted with water and the product was extractedwith ethyl acetate. The combined organic layers were washed with water,brine, and dried over Na₂SO₄. The solvent was removed to give 4.61 g ofcrude 4-(4-ethyl piperazin-1-ylmethyl)-benzoic acid ethyl ester (100%yield). LAH (0.792 g, 20.86 mmol) was taken up in a 3-neck dry flask andTHF (60 mL) was added on cooling. A solution of 4-(4-ethylpiperazin-1-ylmethyl)-benzoic acid ethyl ester (4.61 g, 16.69 mmol) inTHF (10 mL) was added slowly on cooling. After completion of addition,the reaction mixture was heated at reflux for 2 h. The reaction mixturewas cooled to 0° C., 10% NaOH solution was added, and then water wasadded. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water, brine and dried over Na₂SO₄. The solvent was removed to give2.78 g of crude (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol in 78%yield. To a 3-neck flask containing anhydrous CH₂Cl₂ (100 mL) cooled tothe −78° C. oxalyl chloride (1.8 g, 14.25 mmol) and DMSO (1.85 g, 23.76mmol) were added and the mixture was stirred for 15 min at −78° C. Thesolution of (4-(4-ethyl piperazin-1-ylmethyl)phenyl)-methanol (2.78 g,11.88 mmol) in CH₂Cl₂ (10 mL) was added at −78° C. and stirred at −78°C. for 1 h. Then Et₃N (4.8 g, 47.52 mmol) was added at −78° C. Thereaction mixture was allowed to come to room temperature. Water wasadded and the organic layer was separated. The aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withwater, brine and dried over Na₂SO₄. Then, solvent was removed to givecrude 4-(4-ethyl piperazin-1-ylmethyl)benzaldehyde (2.5 g, 91%).

To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and4-(4-ethyl piperazin-1-ylmethyl)benzaldehyde (177 mg, 0.76 mmol) inN,N-dimethyl acetamide (10 mL), NaHSO₃ (150 mg, 0.84 mmol) and p-TSA(319 mg, 1.68 mmol) were added and the reaction mixture was heated at150° C. for 5 h. The reaction mixture was cooled to room temperature,Water was added and the mixture was neutralized with NaHCO₃. The solventwas removed under reduced pressure to give the crude product, which waspurified by column chromatography to give2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxy-quinazolin-4(3H)-one(87 mg, 27%), which was converted to the hydrochloride salt. Selecteddata: MS (ES) m/z: 409.11; MP 278-280° C. (at decomposition).

Example 68

2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one

A mixture of dimethyl acetone-1,3-dicarboxylate (200 g, 1.15 mol),cyanamide (48.3 g, 1.15 mol), and Ni(acac)₂ (14.75 g, 0.0574 mol) indioxane (200 mL) was heated to reflux for 16 h and then cooled to roomtemperature. The precipitate was filtered off, and the solid was mixedwith methanol (200 mL) and stirred for 30 min and filtered again to give93 g product (44% yield). In a 1 L flask with a reflux condenser wasadded the product from step one (93.0 g, 0.505 mol) and POCl₃ (425 mL)and the reaction mixture was heated to reflux for 35 min. POCl₃ (300 mL)was evaporated under vacuum. The residue was poured into ice and water(400 mL), which was neutralized with KOH to pH 6-7. The precipitate wasfiltered off and extracted with ethyl acetate (2×300 mL). The organicsolution was concentrated and purified by column chromatography to givemethyl 2-amino-4,6-dichloropyridine-3-carboxylate (22.5 g, 20.1%). In a500 mL flask with reflux condenser was added methyl2-amino-4,6-dichloropyridine-3-carboxylate (22.5 g, 0.101 mol) and 25 wt% sodium methoxide in methanol (88 mL, 0.407 mol), together withmethanol (20 mL). The mixture was heated to reflux for 5 h then cooledto room temperature. Acetic acid (15 mL) was added to the mixture andthe pH was adjusted to ˜7.0. Methanol was removed and the residue waspoured into water (100 mL). The precipitated solid was filtered off andrinsed with water (3×200 mL) to give methyl2-amino-4,6-dimethoxypyridine-3-carboxylate (18.5 g, 86.4%). In a 500 mLflask with a reflux condenser was added methyl2-amino-4,6-dimethoxypyridine-3-carboxylate (18.5 g, 0.0872 mol),potassium hydroxide (19.5 g, 0.349 mol) in water (80 mL) and ethanol(100 mL). The mixture was heated to 80° C. for 16 h. The solvent wasremoved and aqueous HCl was used to adjust pH to 6.0. The water wasremoved by lyophilization. The obtained solid was extracted withmethanol to yield 2-amino-4,6-dimethoxy-nicotinic acid in quantitativeyield. 2-Amino-4,6-dimethoxy-nicotinic acid (17.2 g, 0.0872 mol) wasadded to THF (110 mL). 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (21.73 g, 0.113 mol), 1-hydroxybenzotriazole hydrate(12.96 g, 0.0959 mol) and 4-methyl morpholine (9.7 g, 0.0959 mol) werethen added to the suspension. After stirring for 10 min at roomtemperature, 50% v/v ammonium hydroxide (18.3 g, 0.262 mol) was added.The reaction mixture was kept at room temperature for 16 h. THF wasremoved and the residue was poured into cold water (100 mL). Theprecipitate was filtered off and further washed with cold water to yield5.3 g of the pure desired compound. The aqueous solution was furtherextracted with dichloromethane (3×150 mL) to yield 8.4 g crude product,which was further purified by column chromatography to give a total of10.8 g (62.8%) of 2-amino-4,6-dimethoxy-nicotinamide.

To a solution of 2-amino-4,6-dimethoxy-nicotinamide (1.40 g, 7.1 mmol)and 4-hydroxy-3,5-dimethylbenzaldehyde (1.07 g, 7.1 mmol) inN,N-dimethyl acetamide (20 mL), NaHSO₃ (1.39 g, 7.81 mmol) and p-TSA(0.675 g, 3.55 mmol) were added and the reaction mixture was heated at150° C. overnight. The solvent was removed under reduced pressure. Theresidue was diluted with water and the solid was collected and furtherwashed with methanol. The crude product was purified by columnchromatography (silica gel 230-400 mesh; 2% methanol in CH₂Cl₂ aseluent) to give2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one(0.92 g, 39.6%). Selected data: MS (ES) m/z: 328.07; MP 297-299° C.

Example 69

5,7-dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one

5,7-Dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-onewas synthesized from 2-amino-4,6-dimethoxybenzamide and4-methoxy-3-morpholin-4-ylmethyl-benzaldehyde, using the methoddescribed for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one.5,7-Dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one(65 mg, 28%) was isolated as a light yellow solid. Selected data: MS(m/z): 412.07; MP 282.7-284.5° C.

Example 70

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one

To a solution of 2-amino-4,6-dimethoxy-nicotinamide (1.07 g, 5.42 mmol)and 4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde(1.67 g, 5.42 mmol) in N,N-dimethyl acetamide (25 mL), NaHSO₃ (1.06 g,5.97 mmol) and p-TSA (1.14 g, 5.97 mmol) were added and the reactionmixture was heated at 150° C. for 16 h, cooled to room temperature andpoured into water. The solid was collected to give 3.25 g of crudeproduct. To a solution of the crude product (3.25 g, 6.70 mmol) in THF(50 mL), TBAF (3.5 g, 13.4 mmol) was added at 0° C. and the mixture wasstirred at room temperature for 1 h. The reaction mixture was quenchedwith water. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water, brine and dried over Na₂SO₄. The solvent was removed, andthe crude was purified by column chromatography (silica gel 230-400mesh; 2% methanol in CH₂Cl₂ as eluent) to give2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one(132 mg, 6%). Selected data: MS (ES) m/z: 371.99; MP 255-256° C.

Example 71

2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H)-one

2-Amino-4,6-dimethoxybenzamide (0.5 g, 2.55 mmol) and methyl iodide(0.17 mL, 2.81 mmol) were mixed in a closed bomb and heated at 110° C.for 14 h. The compound was washed with a dichloromethane-methanolmixture. After removing the solvent, the crude was purified by silicagel column chromatography (40 g) employing 1-5% methanol indichloromethane to give 2,4-dimethoxy-6-methylamino-benzamide (0.027 g,50.4%).

The compound 3,5-dimethyl-4-hydroxybenzoic acid (5.04 g, 30.33 mmol) wasmixed with pyridine (20 mL). Acetic anhydride (3.72 g, 36.4 mmol) wasadded and the mixture was stirred at room temperature for 4 h. Thesolvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoicacid in quantitative yield (6.33 g). The compound4-acetoxy-3,5-dimethyl-benzoic acid (0.36 g, 1.73 mmol)) was dissolvedin dichloromethane (5 mL) and oxalyl chloride (0.3 mL, 3.46 mmol) wasadded dropwise, followed by 1 drop of DMF. The reaction mixture wasstirred at room temperature under nitrogen for 2 h. The solvent wasevaporated in vacuo to obtain acetic acid4-chlorocarbonyl-2,6-dimethyl-phenyl ester in quantitative yield (0.392g).

A solution of 2,4-dimethoxy-6-methylamino-benzamide (0.28 g, 1.33 mmol)in pyridine (10 mL) was added to acetic acid4-chlorocarbonyl-2,6-dimethyl-phenyl ester (1.1 eq.) and stirred at roomtemperature for 14 h. The solvent was removed and the reaction mixturewas acidified with 1 N HCl and extracted with ethyl acetate. The solventwas removed and the crude was purified by silica gel columnchromatography (40 g) employing 1% methanol in dichloromethane to giveacetic acid4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenylester (0.34 g, 67%). Acetic acid4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenylester (0.34 g, 0.89 mmol) was dissolved in ethanol (5 mL), 5% aqueousNaOH solution (10 mL) was added dropwise and the mixture was stirred atroom temperature for 1.5 h. The compound was extracted with ethylacetate and washed with ether to give2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H)-one(0.13 g, 43%). Selected data: MS (ES) m/z: 340.17; MP 188.5-189.1° C.

Example 72

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A solution of 3,5-dimethoxy-4-hydroxybenzaldehyde (3 g, 20 mmol) and1-(2-chloro-ethyl)-pyrrolidine hydrochloride (3.74 g, 22 mmol) in DMF(50 mL) was mixed with sodium hydride (2.24 g, 56 mmol) and potassiumiodide (0.73 g, 4.4 mmol). The reaction mixture was stirred at roomtemperature for 2 h and then at 80° C. for an additional 2 h. Thereaction was quenched with water (50 mL), extracted with EtOAc (3×100mL), concentrated to afford an oily residue. Purification by columnchromatography to yield 3.4 g of3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (70%). A mixtureof 2-amino-4,6-dimethoxy-benzamide (0.2 g, 1.02 mmol),3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (0.251 g, 1.02mmol), sodium hydrogensulfite (0.181 g, 1.02 mmol) and p-toluenesulfonicacid (0.234 g, 1.224 mmol) in N,N-dimethyl acetamide (10 mL) was stirredat 155° C. for 2 h. The reaction mixture was cooled to room temperature,diluted with water (50 mL), extracted with EtOAc (3×50 mL), andconcentrated to afford a solid residue. The solid was further purifiedby column chromatography to yield about 40 mg impure product. This samereaction was repeated three times on the same scale and the impureproduct after each column was combined and subjected to one final columnto yield2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(76 mg, 4%) as a light yellow solid. Selected data: MS (ES) m/z: 424.04;MP 181.0-183.2° C.

Example 73

N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide

To a solution of 2-amino-5-nitro-benzamide (680 mg, 3.75 mmol) and4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (1.16g, 3.75 mmol) in N,N-dimethyl acetamide (35 mL), NaHSO₃ (736 mg, 4.14mmol) and p-TSA (71 mg, 0.375 mmol) were added and the reaction mixturewas heated at 150° C. for 5 h. The solvent was evaporated under reducedpressure. The residue was diluted with water and the solids werefiltered off to give crude product (590 mg, 44%). To a solution of abovecrude product (490 mg, 1.38 mmol) in DMF (20 mL) and MeOH (20 mL),Pd—C(100 mg, 10%) was added and the reaction mixture was hydrogenatedfor 4 h at room temperature at 30 psi H₂. The reaction mixture wasfiltered and the solvent was evaporated to give crude product. The crudewas purified by column chromatography (silica gel 230-400 mesh; 4%methanol in CH₂Cl₂ as eluent) to give 6-amino-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3H-quinazolin-4-one (190 mg, 42% yield). Toa solution of 6-amino-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-3H-quinazolin-4-one (95 mg, 0.29 mmol) inpyridine (5 mL), acetic anhydride (108 mg, 0.73 mmol) was added and themixture was stirred for 16 h at room temperature. The solvent wasremoved and the solids were dissolved in a mixture of MeOH (10 mL) andTHF (10 mL) (compound was partially soluble). Then K₂CO₃ (100 mg, 0.73mmol) was added and the reaction mixture was stirred for 3 h at roomtemperature. The solvent was removed and the crude was purified bycolumn chromatography (silica gel 230-400 mesh; 5% methanol in CH₂Cl₂ aseluent) to giveN-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide

(65 mg, 60%). Selected data: MS (ES) m/z: 368.09; MP>300° C.

Example 74

7-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy-1,6-naphthyridin-5(6H)-one

Malonic acid (5.27 g, 51 mmol), 2,4,6-trichlorophenol (20 g, 100 mmol)and phosphorus oxychloride (17.17 g, 112 mmol) were stirred undernitrogen atmosphere at reflux for 12 h. The reaction mixture was cooledto 70° C. and poured into ice water. The formed precipitate wascollected, washed with water and dried under vacuum to provide thedesired malonic acid bis-(2,4,6-trichloro-phenyl) ester as a white solid(23.37 g, quantitative yield). To a mixture of malonic acidbis-(2,4,6-trichloro-phenyl) ester (23.37 g, 50.5 mmol) andethyl-3-aminocrotonate (6.38 mL, 50.5 mmol) under nitrogen atmospherewas added bromobenzene (5 mL). The reaction mixture was heated underreflux for 2.5 h then cooled to room temperature and diluted with ethylacetate. The formed precipitate was filtered off, washed several timeswith ethyl acetate and dried under vacuum to afford the desired4,6-dihydroxy-2-methyl-nicotinic acid ethyl ester as a yellow solid(13.04 g, quantitative yield). To a mixture of4,6-dihydroxy-2-methyl-nicotinic acid ethyl ester (12.93 g, 65.57 mmol)in N,N-dimethylformamide (550 mL) and potassium carbonate (27.18 g,196.71 mmol) under nitrogen atmosphere was added dropwise isopropyliodide (19.65 mL, 196.71 mmol). The resulting slurry was vigorouslystirred at room temperature overnight and then filtered to removeinsoluble salts. The filtrate was diluted with water (300 mL) andextracted with ethyl acetate (4×400 mL). The combined organic layerswere washed with brine, dried over sodium sulfate and evaporated toafford the desired 4,6-diisopropoxy-2-methyl-nicotinic acid ethyl esteras an oil which solidified on standing (15.24 g, 82.6%). To a solutionof 4,6-diisopropoxy-2-methyl-nicotinic acid ethyl ester (15.24 g, 54.2mmol) in methanol (70 mL) was added sodium hydroxide in water (70 mL).The reaction mixture was heated under reflux for 48 h. The solvent wasremoved under reduced pressure and concentrated hydrochloric acid wasadded (20 mL). The solvent was evaporated to provide the desired4,6-diisopropoxy-2-methyl-nicotinic acid as a white salt (26.91 g,theoretical mass: 13.73 g). To a solution of4,6-diisopropoxy-2-methyl-nicotinic acid salt (13.73 g, 54.2 mmol) inmethylene chloride (160 mL) under nitrogen atmosphere was added oxalylchloride (9.46 mL, 108.4 mmol) followed by N,N-dimethylformamide (1 mL).The reaction mixture was stirred overnight then the solvent wasevaporated to obtain the desired crude acid chloride, which was used forthe next step without further purification. To 50% v/v ammonia hydroxide(500 mL) at room temperature was added dropwise a solution of the crude4,6-diisopropoxy-2-methyl-nicotinoyl chloride in methylene chloride (400mL). The reaction mixture was stirred for 3.5 h. The solution wasseparated and the aqueous layer was extracted with methylene chloride(100 mL×8). The combined organic layers were dried over sodium sulfateand evaporated to afford a crude solid (6.94 g). The crude was purifiedby flash column chromatography to provide pure4,6-diisopropoxy-2-methyl-nicotinamide as an orange solid (3.0 g,21.9%). To a solution of 4,6-diisopropoxy-2-methyl-nicotinamide (0.3 g,1.18 mmol) in THF (5 mL) under nitrogen was added 1.6 M n-BuLi solutionin hexanes (3 mL, 4.75 mmol) at −20° C. The reaction mixture was allowedto warm-up to room temperature and left to stir for 2 h. The reactionwas then cooled to −20° C. and a solution of4-benzyloxy-3,5-dimethyl-benzonitrile in THF (5 mL) was added dropwise.The reaction mixture was allowed to warm to room temperature and wasleft to stir for 20 h. Water and acetic acid were added until pH ˜5. Thesolution was heated to 55° C. for 3 h then cooled to room temperature,diluted with ethyl acetate, separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate and evaporated under reducedpressure to provide crude orange oil (1.02 g). The crude was purified byflash column chromatography to provide pure7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-diisopropoxy-6H-[1,6]naphthyridin-5-oneas a yellow solid (0.10 g, 17.9%). To a solution of7-(4-benzyloxy-3,5-dimethyl-phenyl)-2,4-diisopropoxy-[1,6]naphthyridin-5-ylamine(0.10 g, 0.21 mmol) in methanol (4 mL) was added palladium on charcoalcatalyst (0.06 g, 0.54 mmol). The reaction mixture was stirred under 1atmosphere pressure of hydrogen for 20 h and diluted with methanol andfiltered through a Celite pad. The solvent was evaporated under reducedpressure to provide a crude solid (0.077 g) which was triturated withether followed by methanol to afford the desired compound7-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy-1,6-naphthyridin-5(6H)-one(35 mg, 43.2%). Selected data: MS (ES) m/z: 383.08; MP 206-208° C.

Example 75

2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 3-bromo-4-hydroxybenzaldehyde (5 g, 2.44 mmol) inacetone (100 mL) under nitrogen atmosphere was added potassium carbonate(50 6 g, 36.6 mmol). The slurry mixture was cooled to 0° C. andchloromethyl ether (9.25 mL, 12.2 mmol) was added dropwise. The ice bathwas removed and the mixture was heated at 70° C. for 2.5 h. Aftercooling to room temperature, excess potassium carbonate was filtered offand the acetone evaporated under reduced pressure. The residue wasdissolved in ethyl acetate (300 mL) and water (100 mL) was added. Theorganic layer was separated, washed with 0.5 N sodium hydroxide solution(100 mL×2) followed by brine and dried over sodium sulfate andconcentrated to give a crude oil (6.69 g), which was purified by FlashColumn Chromatography on 230-400 mesh silica gel (40-63 μm particlesize) eluted with EtOAc/hexane: 2/3 to provide pure3-bromo-4-methoxymethoxy-benzaldehyde, as an oil (4.46 g, 73.2%). To asolution of 3-bromo-4-methoxymethoxy-benzaldehyde (4.4 g, 17.9 mmol) andvinyltributyl tin (5.8 mL, 19.7 mmol) in toluene (130 mL) under nitrogenatmosphere was added an catalytic amount oftetrakis(triphenylphosphine)palladium (0.79 mg, 0.68 mmol). Theresulting mixture was heated at 100° C. overnight, cooled to roomtemperature and a saturated potassium fluoride solution (30 mL) wasadded. The solution was stirred for 30 min then diluted with ethylacetate, separated, and the aqueous layer was extracted with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate and evaporated under reduced pressure to provide crudeyellow oil (4.6 g). The crude was purified by flash columnchromatography to give pure 4-methoxymethoxy-3-vinyl-benzaldehyde as ayellow oil (1.95 g, 56.5%). To a solution of4-methoxymethoxy-3-vinyl-benzaldehyde (1.8 g, 9.46 mmol) in THF (25 mL)under nitrogen was added borane dimethyl sulfide complex at 0° C. Thesolution was allowed to warm to room temperature and was stirred for 18h. The reaction mixture was quenched at 0° C. with methanol (12 mL),hydrogen peroxide solution (8 mL) and 4 N sodium hydroxide solution (12mL). The mixture was vigorously stirred at room temperature for 12 h andwas diluted with ethyl acetate. The aqueous layer was extracted withethyl acetate. The combined organic layers were washed with brine, driedover sodium sulfate and evaporated under reduced pressure to providecrude oil (3.2 g). The crude was purified by flash column chromatographyto give pure 2-(5-hydroxymethyl-2-methoxymethoxy-phenyl)-ethanol (1.19g, 59.5%). The mixture of2-(5-hydroxymethyl-2-methoxymethoxy-phenyl)-ethanol (0.78 g, 3.69 mmol)and magnesium dioxide (0.086 g, 0.99 mmol) in chloroform (12 mL) washeated at 80° C. for 3 h under nitrogen. The reaction mixture was cooledto room temperature and was diluted with chloroform and filtered througha Celite pad to give the desired3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.63 g, 81.3%), whichwas used without further purification.

A mixture of 2-amino-4,6-dimethoxy-benzamide (0.25 g, 1.27 mmol),3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.268 g, 1.27 mmol),sodium hydrogensulfite (0.146 g, 1.4 mmol) and p-toluenesulfonic acid(0.025 g, 0.127 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at150° C. overnight under nitrogen atmosphere. The reaction mixture wascooled to room temperature, the solvent evaporated under reducedpressure. Water (70 mL) was added to obtain a solid. The yellow solidwas filtered off, washed with water and dried under vacuum to providecrude2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.182 g, 36.7%) which was used as such in the next step. A solution of2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.18 g), 50% acetic acid solution (4 mL) and catalytic amount ofconcentrated sulfuric acid (0.02 mL) was heated at 70° C. for 2.5 h.After cooling to room temperature the reaction mixture was diluted withwater (30 mL) to obtain a solid. The solid was filtered off, washed withwater and dried under high vacuum to provide crude solid (0.135 g, 85%).The crude was purified by flash column chromatography to give pure2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.035 g. 8% over 2 steps). Selected data: MS (ES) m/z: 343.0; MP249-250.3° C.

Example 76

2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol

To a 100 mL round bottom flask was added 2-amino-4,6-dimethoxy-benzamide(318 mg, 1.6 mmol), 4-(2-benzyloxy-ethoxy)-3,5-dimethyl-benzaldehyde(461 mg, 1.6 mmol), p-toluenesulfonic acid monohydrate (32 mg, 0.16mmol), sodium hydrogensulfite (318 mg, 1.8 mmol) and dimethylacetamide(5 mL). The mixture was stirred in a 150° C. oil bath under nitrogenovernight. Water (40 mL) and ether (30 mL) were added. The precipitatewas filtered off, washed with water then ether, and air-dried. Theintermediate2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-onewas obtained as light brown/beige solid. Yield 474 mg (64%).2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(474 mg, 1.03 mmol) was stirred in phosphorus oxychloride (10 mL) at100° C. for 4 h. Excess phosphorus oxychloride was removed under reducedpressure. Ice was added and the solid was collected. The solid waswashed with water and ether, and air-dried.2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazolinewas obtained as a light brown solid (yield: 356 mg, 72%).2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline(192 mg, 0.4 mmol) was dissolved in a small amount of THF and 10% Pd/C(dry) (66 mg) was added. Anhydrous methanol (20 mL) and ammonium formate(955 mg) were added. The mixture was stirred in a 80° C. oil bath for 5h. The mixture was filtered through Celite, washed with MeOH/DCM,purified by column chromatography to give2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol (36 mg,25%) as an off-white solid. Selected data: MS (ES) m/z: 355.04; mp169-170° C.

Example 77

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one

To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in aceticacid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodiumnitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture wasstirred at 0° C. for 30 min after completion of addition and copper (I)cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixturewas stirred at 0° C. for 5 h and at room temperature for an additional 2h. The mixture was passed through a Celite pad, extracted with EtOAc(3×100 mL), and concentrated using a rotary evaporator to afford a solidresidue. The solid was further purified by column (SiO₂,hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6g, 81%) as a light yellow solid. A solution of2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I)cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14h. The reaction mixture was cooled to room temperature, quenched byadding water (30 mL), filtered through a Celite pad, extracted withEtOAc (3×100 mL), and concentrated using a rotary evaporator to afford asolid residue. The solid was further purified by column (SiO₂,hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile(23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide(10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). Thereaction mixture was stirred at 60° C. for 3 h, diluted with water (100mL), extracted with EtOAc (3×100 mL), and concentrated using a rotaryevaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). Asolution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH(30 mL) was mixed with palladium carbon (0.25 g). The resultingsuspension was stirred at room temperature under hydrogen for 14 h. Themixture was passed through a Celite pad, concentrated using a rotaryevaporator to afford 2-amino-4,6-dimethyl benzamide (0.42 g, 95%).

A mixture of 2-amino-4,6-dimethyl benzamide (0.2 g, 1.22 mmol),4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde(0.376 g, 1.22 mmol), sodium hydrogensulfite (0.22 g, 1.22 mmol) andp-toluenesulfonic acid (0.116 g, 0.61 mmol) in N,N-dimethyl acetamide(10 mL) was stirred at 155° C. for 14 h. The reaction mixture was cooledto room temperature and diluted with water (50 mL). The solid crashedout and was collected by filtration to afford impure product. The solidwas re-dissolved in THF (30 mL) and mixed with TBAF in THF (5 mL, 5mmol). The reaction mixture was stirred at room temperature for 14 h andconcentrated using a rotary evaporator to afford an oily residue.Further purification by column (SiO₂, EtOAc/DCM/MeOH=12:4:1) yielded anoff-white solid. This solid was diluted with MeOH (10 mL) to make aslurry. The solid was collected by filtration and washed with MeOH toafford2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one(98 mg, 24%) as a white solid. Selected data: MS (ES) m/z: 339.10; MP259.6-261.2° C.

Example 78

2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-pyrido[2,3-d]pyrimidin-4(3H)one

To a solution of 2-amino-4,6-dimethoxy-nicotinamide (300 mg, 1.52 mmol)and 4-(bis-(2-hydroxyethyl)amino)-benzaldehyde (318 mg, 1.52 mmol) inN,N-dimethylacetamide (10 mL) were added NaHSO₃ (297 mg, 1.67 mmol) andp-TSA (376 mg, 1.98 mmol) and the reaction mixture was heated at 150° C.for 4 h, cooled to room temperature, and concentrated under reducedpressure. The residue was diluted with water and the solid was filteredoff to give the crude product. The crude product was purified by columnchromatography to give2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one(60 mg, 10%). Selected data: MS (ES) m/z: 387.05; MP 277-279° C.

Example 79

5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one

To a solution of 3,5-dimethyl-4-hydroxy benzaldehyde (2.0 g, 13.33 mmol)in DMF was added NaH (640 mg, 16.0 mmol, 60% in oil) and the mixture wasstirred for 1 h at room temperature. A solution of 1-bromo-2-methoxyethane (1.85 g, 13.33 mmol) was added and the mixture was stirred for 72h at room temperature. The reaction mixture was quenched by addition ofsaturated NH₄Cl solution and diluted with water. The product wasextracted with ethyl acetate. The combined organic layers were washedwith water, brine and dried over Na₂SO₄. Upon removal of solvent, itgave 2.1 g of 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (76 yield).To a solution of 2-amino-4,6-dimethoxy-benzamide (200 mg, 1.02 mmol) and4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (212 mg, 1.02 mmol) inN,N-dimethyl acetamide (10 mL), NaHSO₃ (199 mg, 1.12 mmol) and p-TSA (22mg, 0.102 mmol) were added and the reaction mixture was heated at 150°C. for 3 h. Cooled to room temperature and the solvent was evaporatedunder reduced pressure. The residue was diluted with water and the solidwas collected to give the crude product. The crude product was purifiedby chromatography using 2% MeOH in CH₂Cl₂ to give5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one(170 mg, 43%). Selected data: MS (ES) m/z: 385.10; MP 201-202° C.

Example 80

5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one

To a solution of 2-amino-4,6-dichloro-benzoic acid (0.5 g, 2.43 mmol) inTHF (22 mL) under nitrogen atmosphere was added successivelyN-(3-Dimehtylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.51 g,2.67 mmol), N-hydroxybenzotriazole (0.36 g, 2.67 mmol) andN-methylmorpholine (0.3 mL, 2.67 mmol). The mixture was stirred for 1.5h before a 50% ammonium hydroxide solution (1.03 mL, 14.58 mmol) wasadded. The mixture was stirred overnight. The solvent was evaporatedunder reduced pressure, water (20 mL) was added and the solution wasextracted with EtOAc (50 mL×2). The combined organic layers were washedwith water, brine, dried over sodium sulfate and evaporated underreduced pressure to provide crude yellow solid (0.45 g). The crudeproduct was triturated with ether to give pure2-amino-4,6-dichloro-benzamide (0.41 g, 82%). A mixture of2-amino-4,6-dichloro-benzamide (0.2 g, 0.97 mmol),4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde(0.3 g, 0.97 mmol), sodium hydrogensulfite (0.11 g, 1.05 mmol) andp-toluenesulfonic acid (0.093 g, 0.48 mmol) in N,N-dimethyl acetamide (8mL) was stirred at 150° C. overnight under nitrogen atmosphere. Thereaction mixture was cooled to room temperature, the solvent wasevaporated under reduced pressure, then water (70 mL) was added and theprecipitate was collected, and washed with water, dried under vacuum andtriturated with ether to provide the crude mixture of2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-5,7-dichloro-3H-quinazolin-4-oneand5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-one(0.298 g), which was used as such in the next step. To the abovedescribed mixture (0.298 g, 0.59 mmol) in tetrahydrofurane (5 mL) wasadded tetrabutylammonium fluoride (2.35 mL, 2.35 mmol) under nitrogenatmosphere. The reaction mixture was stirred overnight before thesolvent was evaporated under reduced pressure and water was added toobtain a precipitate. The solid was filtered off, washed with water,dried under vacuum and triturated with ether to provide crude yellowsolid (0.226 g, 98%). The crude was purified twice by flash columnchromatography to give pure5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one(0.069 g, 19%). Selected data: MS (ES) m/z: 378.92, 380.88, 382.89; MP260.8-262.6° C.

Example 81

2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one

To a solution of 2,6-dimethoxytoluene (50 g, 328.5 mmol) in ether (450mL) was added freshly prepared dioxane dibromide in ether over 0.5 h.The mixture was stirred at room temperature for an additional 1.5 h andpoured into a beaker containing water (500 mL). The aqueous layer wasdiscarded and the ether layer was washed sequentially with water (2×500mL), sodium bicarbonate (saturated aqueous) (2×500 mL), dried oversodium sulfate, and concentrated using a rotary evaporator to afford 76g of 3-bromo-2,6-dimethoxytoluene as a colorless oil (100%). A coolingwell was used to collect 300 mL of ammonia at −78° C., which was mixedwith potassium (0.5 g) and ferric nitrate (0.5 g). Additional potassium(14.2 g, 364 mmol) was added at −78° C. portion-wise. The solution wasstirred at −78° C. for 15 min. To this solution was slowly added3-bromo-2,6-dimethoxytoluene (42 g, 182 mmol) in THF (100 mL). Theresulting mixture was stirred at −78° C. for 3 h and then 0° C. for 1 h.The reaction was quenched by adding water (150 mL) and extracted withDCM (3×200 mL) to get a brown oil as the crude product. It was furtherpurified by column chromatography to yield 22.1 g of3,5-dimethoxy-4-methylaniline (73%). A solution of3,5-dimethoxy-4-methylaniline (22.1 g, 132.3 mmol) in dioxane (380 mL)and water (380 mL) was mixed with potassium carbonate (45.6 g, 330.8mmol) and (Boc)₂O (34.6 g 158.8 mmol) and stirred at room temperaturefor 14 h. The reaction mixture was then extracted with DCM (3×100 mL)and concentrated using a rotary evaporator. The resulting solid residuewas purified by column chromatography. A mixture of DCM-hexanes (20mL-300 mL) was used to make a slurry and the solid was collected byfiltration and washed with hexanes to provide 28.6 g of(3,5-dimethoxy-4-methyl-phenyl)-carbamic acid tert-butyl ester (81%). Asolution of (3,5-dimethoxy-4-methyl-phenyl)-carbamic acid tert-butylester (28.6 g, 107.1 mmol) in carbon tetrachloride (450 mL) was mixedwith NBS (19.05 g, 107.1 mmol) and AIBN (1.55 g, 9.37 mmol) and themixture was stirred at 80° C. with the light on for 2 h. The reactionwas quenched by adding water (150 mL) and extracted with DCM (3×100 mL),and concentrated to afford a solid residue. Further purification bycolumn chromatography yielded 34.9 g of(2-bromo-3,5-dimethoxy-4-methyl-phenyl)-carbamic acid tert-butyl ester(94%). A solution of (2-bromo-3,5-dimethoxy-4-methyl-phenyl)-carbamicacid tert-butyl ester (34.9 g, 100.9 mmol) in carbon tetrachloride (450mL) was mixed with NBS (21.5 g, 121.0 mmol) and AIBN (1.55 g, 9.37 mmol)and was stirred at 80° C. with the light on for 4 h. The reaction wasthen quenched by adding water (150 mL) and extracted with DCM (3×100mL), and concentrated to afford a solid residue. Further purification bycolumn chromatography yielded 39 g of(2-bromo-4-bromomethyl-3,5-dimethoxy-phenyl)-carbamic acid tert-butylester (91%). A solution of(2-bromo-4-bromomethyl-3,5-dimethoxy-phenyl)-carbamic acid tert-butylester (39 g, 91.8 mmol) in THF (600 mL) was mixed with morpholine (45mL, 515.0 mmol) and stirred at room temperature for 7 h. The reactionwas diluted with water (300 mL), extracted with DCM (3×200 mL), andconcentrated using a rotary evaporator. The residue was further purifiedby column (SiO₂, DCM/MeOH=20:1) to provide 35 g of(2-bromo-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acidtert-butyl ester (88%). A solution of(2-bromo-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acidtert-butyl ester (3 g, 6.94 mmol) in THF (150 mL) was mixed with NaH(0.333 g, 8.33 mmol) and stirred at room temperature for 1.5 h. Theresulting mixture was cooled to −78° C. and mixed with nBuLi (3.33 mL,8.33 mmol). The reaction was stirred for 1.5 h at −78° C. beforeaddition of t-BuLi (8.16 mL, 13.88 mmol). The reaction was stirred at−78° C. for 1 h and carbon dioxide gas was then bubbled through for 8 hallowing the temperature to rise gradually to room temperature. Thereaction was quenched by adding water (0.5 mL, 27.8 mmol) andconcentrated using a rotary evaporator. The solid residue was made intoslurry in minimal amount of MeOH and the solid was filtered off. Thefiltrate was then concentrated using a rotary evaporator and the solidwas made into a slurry again in MeOH and filtered. After repeating twoto three times, the filtrate was concentrated to yield 1.1 g of impure6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoicacid (40% crude yield).

A solution of6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoicacid (1.8 g, 4.54 mmol), EDCl.HCl (1.31 g, 6.82 mmol), HOBt (1.23 g,9.09 mmol), and triethylamine (3.3 mL, 23.7 mmol) in THF (50 mL) wasstirred at room temperature for 1 h. Ammonium hydroxide (50% aqueous, 10mL) was then added to the reaction mixture. The resulting mixture wasstirred at room temperature for 6 h. The reaction was quenched by addingwater (50 mL), extracted with DCM (3×100 mL), and concentrated using arotary evaporator. The residue was further purified by column (SiO₂,DCM/MeOH/EtOAc=2:1:4) to provide 0.9 g of(2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acidtert-butyl ester (50%). A solution of(2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acidtert-butyl ester (0.9 g, 2.74 mmol) in HOAc (20 mL) and 12 N HCl aqueous(20 mL) was stirred at 50° C. for 1 h and then concentrated to drynessusing a rotary evaporator. The residue was mixed with saturated sodiumbicarbonate aqueous (40 mL), extracted with DCM (3×100 mL), andconcentrated. The residue was further purified by column (SiO₂,DCM/MeOH/EtOAc=3:2:3) to provide 0.6 g of6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (89%). A mixtureof 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (0.6 g, 2.03mmol), 3,5-dimethyl-4-hydroxy benzaldehyde (0.61 g, 4.06 mmol), sodiumhydrogensulfite (1.24 g, 7.0 mmol) and p-toluenesulfonic acid (1.14 g, 6mmol) in N,N-dimethyl acetamide (20 mL) was stirred at 115° C. for 6 h.The reaction mixture was cooled to room temperature, diluted with water(50 mL), extracted with EtOAc, and concentrated. Purification by columnchromatography afforded a solid residue, which was made into slurry in amixed solvent of DCM-hexanes (3 mL-20 mL). The slurry was filtered andwashed with hexanes to provide2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one(56 mg, 6.6%) as a light yellow solid. Selected data: MS (ES) m/z:426.0; MP 237.0-239.1° C.

Example 82

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one

Following the method described for6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one,2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-onewas made from 2-amino-5-methoxybenzamide and4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylbenzaldehyde in 4%yield and isolated as a white solid. Selected data: ¹H NMR (300 MHz,DMSO-d₆) δ 12.28 (s, 1H), 7.88 (s, 2H), 7.68 (d, J=8.90 Hz, 1H), 7.53(d, J=2.95 Hz, 1H), 7.43 (dd, J=8.90, 2.98 Hz, 1H), 4.89 (t, J=5.52 Hz,1H), 3.92-3.80 (m, 5H), 3.73 (q, J=5.09, 5.09, 4.97 Hz, 2H), 2.32 (s,6H); MS (APCI) m/z 341 [M+H]⁺.

Example 83

2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A mixture of 2-chlorobenzaldehyde (0.0430 g, 306 mmol),2-amino-4,6-dimethoxybenzamide (0.0600 g, 0.306 mmol), NaHSO₃ (94%,0.0474 g, 0.428 mmol), and p-TsOH.H₂O (0.0175 g, 0.0918 mmol) in DMA(3.06 mL) was heated at 140° C. for 16 h. The mixture was cooled andchromatographed on silica gel, fractions containing the product werecombined, concentrated under vacuum, diluted with EtOAc (300 mL), washedwith water (3×75 mL), brine (75 mL), dried over sodium sulfate, filteredand concentrated under vacuum to provide2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0377 g, 39%) asa yellow solid. Selected data: ¹H NMR (300 MHz, DMSO-d₆) δ 12.14 (s,1H), 7.65-7.40 (m, 4H), 6.72 (d, J=2.29 Hz, 1H), 6.59 (d, J=2.30 Hz,1H), 3.87 (s, 3H), 3.85 (s, 3H); MS (APCI) m/z 317 [M+H]⁺.

Example 84

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one

Following the method described for6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one,2-(4-(2-Hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-onewas made from 2-amino-6-methoxybenzamide (made from the correspondingamino acid in two steps) and4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylbenzaldehyde in 77%yield and isolated as a white solid. Selected data: ¹H NMR (300 MHz,DMSO-d₆) δ ppm 11.96 (s, 1H), 7.89 (s, 2H), 7.68 (t, J=8.20 Hz, 1H),7.23 (d, J=7.89 Hz, 1H), 6.98 (d, J=8.19 Hz, 1H), 4.89 (t, J=5.53 Hz,1H), 3.94-3.65 (m, 7H), 2.31 (s, 6H); MS (APCI) m/z 341 [M+H]⁺.

Example 85

5,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one

A mixture of 2-amino-4,6-dimethoxybenzamide (0.060 g, 0.306 mmol),2-methylbenzaldehyde (0.037 g, 0.306 mmol), NaHSO₃ (0.032 g, 0.306mmol), and p-TsOH.H₂O (0.00370 g, 0.021 mmol) in DMA (5.00 mL) washeated at 60° C. overnight. The mixture was cooled to room temperature,water (50.0 mL) and EtOAc (50.0 mL) was added. The layers were separatedand the organic layer was washed with water (2×50 mL), brine (50 mL),dried and concentrated. The crude solid was purified via CombiFlashprovide 5,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one (0.025 g, 28%) asyellow solid. Selected data: ¹H NMR (300 MHz, CDCl₃) δ 9.51 (s, 1H),7.53 (dd, J=5.92, 3.07 Hz, 1H), 7.46-7.36 (m, 1H), 7.32 (dd, J=9.04,4.60 Hz, 2H), 6.81 (d, J=2.29 Hz, 1H), 6.49 (d, J=2.28 Hz, 1H), 3.95 (s,J=7.48 Hz, 3H), 3.94-3.88 (s, 3H), 2.51 (s, 3H); MS (APCI) m/z 297[M+H]⁺.

Example 86

5,7-dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

Following the procedure described above for2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one,5,7-dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-onewas made from 6-(4-(methylsulfonyl)phenyl)picolinaldehyde and2-amino-4,6-dimethoxybenzamide in 38% as a yellow solid. Selected data:¹H NMR (300 MHz, DMSO-d₆) δ 11.75 (s, 1H), 8.69 (d, J=8.38 Hz, 2H), 8.46(d, J=7.72 Hz, 1H), 8.33 (d, J=7.75 Hz, 1H), 8.22 (t, J=7.84 Hz, 1H),8.08 (d, J=8.37 Hz, 2H), 6.85 (s, 1H), 6.63 (s, 1H), 3.95 (s, 3H), 3.90(s, 3H), 3.4 (s, 3H); MS (APCI) m/z 438 [M+H]⁺.

Example 87

5,7-dimethoxy-2-(6-methylpyridin-2-yl)quinazolin-4(3H)-one

Following the method described for2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one,5,7-dimethoxy-2-(6-methylpyridin-2-yl)quinazolin-4(3H)-one was made from6-methylpicolinaldehyde and 2-amino-4,6-dimethoxybenzamide in 33% yieldand isolated as an off-white solid. Selected data: ¹H NMR (300 MHz,DMSO-d₆) δ 11.00 (s, 1H), 8.21 (d, J=7.74 Hz, 1H), 7.95 (t, J=7.75 Hz,1H), 7.52 (d, J=7.62 Hz, 1H), 6.82 (d, J=2.33 Hz, 1H), 6.60 (d, J=2.31Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.62 (s, 3H); MS (APCI) m/z 298[M+H]⁺.

Example 88

5,7-dimethoxy-2-(6-(4-(methylthio)phenyl)pyridin-2-yl)quinazolin-4(3H)-one

Following the procedure described above for2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one,5,7-dimethoxy-2-(6-(4-(methylthio)phenyl)pyridin-2-yl)quinazolin-4(3H)-onewas made from 6-(4-(methylthio)phenyl)picolinaldehyde and2-amino-4,6-dimethoxybenzamide in 39% as a white solid. Selected data:¹H NMR (300 MHz, DMSO-d₆) δ 11.51 (s, 1H), 8.39-8.30 (m, 3H), 8.23-8.05(m, 2H), 7.46-7.37 (m, 2H), 6.84 (d, J=2.33 Hz, 1H), 6.62 (d, J=2.33 Hz,1H), 3.92 (s, 3H), 3.88 (s, 3H), 2.55 (s, 3H); MS (APCI) m/z 406 [M+H]⁺.

Example 89

2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one

Following the method described for5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one,2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one wassynthesized from 2-amino-4,6-dimethoxybenzamide and2-chloro-6-methylisonicotinoyl chloride in 75% yield as a white solid.Selected data: ¹H NMR (300 MHz, CDCl₃) δ 10.95 (s, 1H), 7.90 (s, 2H),6.74 (d, J=2.33 Hz, 1H), 6.51 (d, J=2.32 Hz, 1H), 3.88 (s, 3H), 3.86 (s,3H), 2.29 (s, 3H); MS (APCI) m/z 332 [M+H]⁺.

Example 90

5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one

To a solution of 4-methoxy-3,5-dimethylbenzoic acid (0.100 g, 0.555mmol) in CH₂Cl₂ (2.77 mL) cooled to 0-5° C. was added oxalyl chloride(67.8 μL, 0.777 mmol) followed by drop-wise addition of DMF (4.3 μL,0.056 mmol). The mixture was stirred for 50 min, the volatiles wereremoved under vacuum, and the crude acid chloride was used immediatelywithout further purification.

To a mixture of 2-amino-4,6-dimethoxybenzamide (0.0990 g, 0.555 mmol)and pyridine (44.9 μL, 0.555 mmol) in THF (2.02 mL) was added dropwise asolution of the acid chloride (crude residue described above) in THF(925 μL). After 16 h, the mixture was diluted with EtOAc (300 mL),washed with saturated aqueous NH₄Cl (3×75 mL), saturated aqueous NaHCO₃(3×75 mL), and brine (75 mL). The insoluble yellow solid was isolated byfiltration to provide the amide (0.150 g, 83%). A mixture of the amide(0.148 g, 0.413 mmol) and 2 M NaOH (7.00 mL) was heated at 85° C. for 19h, cooled to 5° C., and neutralized with 4 M HCl in dioxanes. The whitesolid was filtered and rinsed with acetone to provide5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one(0.144 g, 100%). Selected data: ¹H NMR (300 MHz, CDCl₃) δ 11.00 (s, 1H),7.90 (s, 2H), 6.74 (d, J=2.33 Hz, 1H), 6.51 (d, J=2.32 Hz, 1H), 3.88 (s,3H), 3.86 (s, 3H), 3.72 (s, 3H), 2.29 (s, 6H); MS (APCI) m/z 341 [M+H]⁺.

Example 91

2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 3,5-dimethyl-4-nitrobenzoic acid (1.00 g, 5.12 mmol) inCH₂Cl₂ (25.6 mL) cooled to 0-5° C. was added oxalyl chloride (0.626 mL,7.17 mmol) followed by dropwise addition of DMF (39.8 μL). The mixturewas stirred for 2 h, the volatiles were removed under vacuum, and thecrude acid chloride was used immediately without further purification.To a mixture of 2-amino-4,6-dimethoxybenzamide (0.913 g, 4.65 mmol) andpyridine (414 μL, 5.12 mmol) in THF (18.6 mL) was added dropwise asolution of the acid chloride (crude residue described above) in THF(8.53 mL). After 16 h, the mixture was diluted with EtOAc (500 mL),washed with saturated aqueous NH₄Cl (3×100 mL), saturated aqueous NaHCO₃(3×100 mL), and brine (100 mL). The insoluble yellow solid was isolatedby filtration to provide the amide (1.51 g, 87%). A mixture of the amide(1.50 g, 4.03 mmol) and 2 M aqueous NaOH (25.0 mL) was heated at 85° C.for 17 h, then added THF (50 mL) and stirred at reflux for 25 h. Thevolatiles were removed under vacuum, the mixture was cooled to 5° C.,and neutralized with 4 M HCl in dioxanes. After stirring for 30 min, thewhite solid was filtered and lyophilized from MeCN/H₂O to afford thecyclized compound (1.36 g, 95%). A mixture of the cyclized compound(0.200 g, 0.563 mmol), Na₂S₂O₄ (0.980 g, 5.63 mmol), water (5.00 mL) andMeOH (15.0 mL) was stirred at 70° C. for 2 h. The volatiles were removedunder vacuum, then diluted with EtOAc (200 mL), washed with saturatedNaHCO₃ (2×100 mL) and brine (75 mL). The organic layer was dried oversodium sulfate, filtered, and the volatiles were removed under vacuum toprovide 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.062 g, 34%) as a yellow solid. Selected data: ¹H NMR (300 MHz,DMSO-d₆) δ 11.45 (s, 1H), 7.78 (s, 2H), 6.66 (d, J=2.25 Hz, 1H), 6.42(d, J=2.24 Hz, 1H), 5.26 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 2.14 (s,6H); MS (APCI) m/z 326 [M+H]⁺.

Example 92

2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A mixture of 2-amino-4,6-dimethoxybenzamide (0.0700 g, 0.36 mmol) and3,5-dimethylbenzoyl chloride (0.112 g, 0.65 mmol) in THF (5.0 mL) wasplaced in a microwave reactor at 80° C. for 30 min. The THF was removedunder reduced pressure, and the residue was purified via CombiFlashchromatography to yield the expected amide. This material was useddirectly in the next step. A mixture of the amide and H₂O/MeCN (2:1,5.00 mL) was basified to pH 12 with 2 N NaOH and stirred at 80° C. for16 h. The mixture was cooled and neutralized with 1 N HCl. The resultingprecipitate was collected on a frit, washed with water (5.00 mL) andlyophilized to yield2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0395 g, 31%over two steps) as a white solid. Selected data: ¹H NMR (300 MHz,DMSO-d₆) δ 11.88 (s, 1H), 7.80 (s, 2H), 7.21 (s, 1H), 6.76 (d, J=2.24Hz, 1H), 6.53 (d, J=2.21 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.35 (s,6H); MS (APCI) m/z 311 [M+H]⁺.

Example 93

(E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide

To a solution of2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.096g, 0.295 mmol) and diisopropylethylamine (61.7 μL, 0.354 mmol), in DMF(2.96 mL) was added dropwise methanesulfonyl chloride (25.2 μL, 0.325mmol). After stirring at room temperature for 18 h, the mixture wasdiluted with EtOAc (300 mL), washed with saturated aqueous sodiumbicarbonate (2×75 mL), saturated aqueous LiCl (2×75 mL), dried oversodium sulfate, filtered and concentrated under vacuum. The residue waspurified over silica gel (12 g, CH₂Cl₂/CH₃OH) to provide(E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide(0.0502 g, 45%) as a white solid. Selected data: ¹H NMR (300 MHz,DMSO-d₆) δ 11.68 (s, 1H), 7.87 (s, 2H), 7.40 (s, 1H), 6.72 (d, J=2.31Hz, 1H), 6.48 (d, J=2.31 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.97 (s,6H), 2.12 (s, 6H); MS (APCI) m/z 381 [M+H]⁺.

Example 94

6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one

To a solution of 4-hydroxy-3,5-dimethylbenzoic acid (2.00 g, 12.0 mmol)in CH₂Cl₂ (60.2 mL) cooled to 0-5° C. was added oxalyl chloride (1.47mL, 16.8 mmol) followed by dropwise addition of DMF (93.3 μL, 1.20mmol). The mixture was stirred for 1.25 h, the volatiles were removedunder vacuum to give crude acid chloride, which was used immediatelywithout further purification. A mixture of 2-amino-5-bromobenzamide(1.99 g, 9.23 mmol) and the acid chloride (crude residue describedabove) in THF (92.3 mL) was stirred at room temperature for 17 h, thenheated at reflux for 4 h. The volatiles were removed under vacuum, theresidue was triturated with EtOAc, and filtered to afford the amide(3.02 g, 90%) as a yellow solid. A mixture of the amide (3.01 g, 8.29mmol), 2 M NaOH (20.0 mL), water (40.0 mL), and MeCN (20.0 mL) washeated at reflux for 15 h, cooled to 5° C., and neutralized with 2 Maqueous HCl. After stirring for 30 min, the white solid was filtered,triturated with acetone, and filtered again to afford6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (2.28 g,80%). Selected data: ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (d, J=2.29 Hz,1H), 7.93 (dd, J=8.72, 2.42 Hz, 1H), 7.86 (s, 2H), 7.63 (d, J=8.70 Hz,1H), 5.75 (s, 1H), 2.24 (s, 6H); MS (APCI) m/z 346 [M+H]⁺.

Example 95

6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one(left) And6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one(right)

A mixture of 2-amino-5-bromobenzamide (0.100 g, 0.465 mmol),4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylbenzaldehyde (0.143 g,0.465 mmol), NaHSO₃ (94%, 0.0515 g, 0.465 mmol), and p-TsOH.H2O (0.00885g, 0.0465 mmol) in DMA (5.81 mL) was heated at reflux for 15 min, cooledto room temperature, the water (20 mL) was added. The precipitate wasfiltered, washed with water, triturated with acetone and filtered again.The crude solid was chromatographed on silica gel (CH₂Cl₂/CH₃OH) toprovide6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one(0.0395 g, 22%) and6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one(0.0227 g, 10%) as white solids. Selected data for6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one:¹H NMR (300 MHz, DMSO-d₆) δ 12.48 (s, 1H), 8.20 (d, J=2.34 Hz, 1H),8.01-7.80 (m, 3H), 7.66 (d, J=8.72 Hz, 1H), 4.90 (t, J=5.46 Hz, 1H),3.85 (t, J=4.87 Hz, 2H), 3.73 (dd, J=10.06, 5.11 Hz, 2H), 2.32 (s, 6H);MS (APCI) m/z 345 [M+H]⁺. Selected data for6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one:¹H NMR (300 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.20 (d, J=2.34 Hz, 1H), 7.95(dd, J=8.71, 2.41 Hz, 1H), 7.90 (s, 2H), 7.67 (d, J=8.72 Hz, 1H), 3.90(m, 4H), 2.32 (s, 6H), 0.90 (s, 9H), 0.09 (s, 6H); MS (APCI) m/z 503[M+H]⁺.

Example 96

2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

Following the method described for2-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one,compound2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onewas synthesized from 2-amino-4,6-dimethoxybenzamide and4-(benzyloxy)-3,5-dimethylbenzoyl chloride in 7% yield as a white solid.Selected data: ¹H NMR (300 MHz, DMSO-d₆) δ 11.84 (s, 1H), 7.93 (s, 2H),7.57-7.33 (m, 5H), 6.75 (d, J=2.28 Hz, 1H), 6.52 (d, J=2.27 Hz, 1H),4.88 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 2.31 (s, 6H); MS (APCI) m/z417 [M+H]⁺.

Example 97

2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A mixture of 3-methyl-4-hydroxybenzaldehyde (0.200 g, 1.5 mmol),(2-bromoethoxy)-tert-butyldimethylsilane (0.538 g, 2.25 mmol) and sodiumhydride (0.061 g, 2.55 mmol) in DMF (5.00 mL) was stirred open at roomtemperature for 30 min in a microwave vial. The vial was then capped andheated in the microwave reactor for 1 h at 80° C. Water (55.0 mL) wasadded to quench. The solution was diluted with 1 N HCl (25.0 mL) andextracted with EtOAc (2×25.0 mL), dried and evaporated. The crudematerial was purified via CombiFlash to yield the alkylated aldehyde. Amixture of 2-amino-4,6-dimethoxybenzamide (0.167 g, 0.85 mmol),4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylbenzaldehyde (0.250 g,0.85 mmol), p-TsOH.H₂O (0.016 g, 0.085 mmol) and NaHSO₃ (0.088 g, 0.85mmol) in DMA (5.00 mL) was stirred at 155° C. for 90 min. The solutionwas diluted with EtOAc (150 mL), washed with saturated NaHCO₃ (2×50 mL),1 N HCl (2×75 mL), brine (50 mL), dried and the solvent was removedunder reduced pressure to yield the TBS protected material (0.068 g,17%) as a tan solid. The crude material was used directly in the nextstep. The TBS-protected material (0.068 g, 0.144 mmol) and 1 M TBAF inTHF (1.00 mL, 7 mmol) was stirred at room temperature for 1 h. Thevolatiles were removed under vacuum, and the residue diluted with EtOAc(100 mL). The solution was washed with water (2×50.0 mL), brine (50.0mL), dried and the solvent was removed. The residue was purified viaCombiFlash to yield2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.024 g, 47%) as an orange solid. Selected data: ¹H NMR (300 MHz,DMSO-d₆) δ 11.81 (s, 1H), 8.05 (m, 2H), 7.05 (d, 1H, J=8.3 Hz), 6.72 (d,1H, J=2.2 Hz), 6.50 (d, 1H, J=2.2 Hz), 4.87 (t, 1H, J=5.5 Hz), 4.09 (t,2H, J=4.9 Hz), 3.89 (s, 3H), 3.84 (s, 3H), 3.76 (dd, 2H, J=5.1 Hz,J=10.0 Hz), 2.24 (s, 3H); MS (APCI) m/z 357 [M+H]⁺.

Example 98

2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A mixture of 4-hydroxy-3-methylbenzaldehyde (0.200 g, 1.47 mmol),2-amino-4,6-dimethoxybenzamide (0.288 g, 1.47 mmol), NaHSO₃ (94%, 0.163g, 1.47 mmol), and p-TsOH.H₂O (0.028 g, 0.147 mmol) in DMA (18.4 mL) washeated at reflux for 1 h. The mixture was diluted with EtOAc (300 mL),washed with saturated aqueous NH₄Cl (2×150 mL) and brine (75 mL), driedover sodium sulfate, filtered and concentrated under vacuum. The residuewas triturated with MeOH and filtered off a yellow solid, which wasfreeze-dried from MeCN/H₂O to provide2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.161 g,35%). Selected data: ¹H NMR (300 MHz, DMSO-d₆) δ 11.71 (s, 1H), 10.02(s, 1H), 7.99 (d, J=1.88 Hz, 1H), 7.89 (dd, J=8.47, 2.29 Hz, 1H), 6.86(d, J=8.50 Hz, 1H), 6.69 (d, J=2.31. Hz, 1H), 6.48 (d, J=2.31 Hz, 1H),3.88 (s, 3H), 3.86 (s, 3H), 2.18 (s, 3H); MS (APCI) m/z 313 [M+H]⁺.

Example 99

N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide(left) And2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(right)

A mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (0.600 g, 4.00 mmol),N-(2-bromoethyl)-phthalimide (1.22 g, 4.80 mmol), K₂CO₃ (0.829 g, 6.00mmol), NaI (3.00 g, 20.0 mmol) in DMF (40.0 mL) was heated at 80° C. for2.5 h. The reaction was cooled to room temperature, diluted with EtOAc(200 mL), washed with 1 M NaOH (2×100 mL), 1 M HCl (2×100 mL), brine (75mL), dried over sodium sulfate, filtered and concentrated under vacuum.The residue was chromatographed on silica gel (40 g, hexanes/EtOAc) toprovide the expected ether (0.300 g, 23%) as a yellow solid. A mixtureof the above ether (0.293 g, 0.907 mmol), 2-amino-4,6-dimethoxybenzamide(0.178 g, 0.907 mmol), NaHSO₃ (94%, 0.100 g, 0.907 mmol), and p-TsOH.H₂O(0.0173 g, 0.0907 mmol) in DMA (11.3 mL) was stirred at reflux for 1.5 hthen cooled to room temperature. The mixture was diluted with EtOAc (250mL), washed with saturated aqueous ammonium chloride (3×75 mL) and brine(75 mL), dried over sodium sulfate, filtered and concentrated undervacuum. The residue was chromatographed on silica gel (40 g,CH₂Cl₂/CH₃OH) to provide the expected product (0.075 g, 17%) as a lightyellow solid. A mixture of the above compound (0.213 g, 0.426 mmol) and2 M methylamine in THF (25.0 mL) was stirred at room temperature for 17h. The volatiles were removed under vacuum and the residue waschromatographed on silica gel to provide compoundN1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide(0.0493 g, 22%) and compound2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.0360 g, 23%) as white solids. Selected data forN1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide:¹H NMR (300 MHz, DMSO-d₆) δ 11.80 (s, 1H), 8.51 (t, J=5.57 Hz, 1H), 8.18(q, J=4.57 Hz, 1H), 7.89 (s, 2H), 7.53-7.42 (m, 4H), 6.74 (d, J=2.31 Hz,1H), 6.52 (d, J=2.29 Hz, 1H), 3.96-3.80 (m, 8H), 3.61 (q, J=5.73 Hz,2H), 2.71 (d, J=4.62 Hz, 3H), 2.32 (s, 6H); MS (APCI) m/z 531 [M+H]⁺.Selected data for2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one:¹H NMR (300 MHz, DMSO-d₆) δ 7.90 (s, 2H), 6.74 (d, J=2.31 Hz, 1H), 6.51(d, J=2.32 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.77 (t, J=5.76 Hz, 2H),2.91 (t, J=5.75 Hz, 2H), 2.30 (s, 6H); MS (APCI) m/z 370 [M+H]⁺.

Example 100

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide

A mixture of2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.060 g, 0.162 mmol), 4-methoxybenzenesulfonyl chloride (0.044 mg,0.211 mmol), and triethylamine (29.4 μL, 0.211 mmol) in CH₂Cl₂ (812 μL)was stirred at room temperature for 3 h. The mixture was chromatographeddirectly on silica gel to yieldN-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide(0.046 g, 53%) as a white solid after lyophilization from MeCN/H₂O.Selected data: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.81 (s, 1H), 7.88 (s,2H), 7.83-7.73 (m, 3H), 7.17-7.07 (m, 2H), 6.73 (d, J=2.31 Hz, 1H), 6.52(d, J=2.29 Hz, 1H), 3.91-3.75 (m, 11H), 3.12 (q, J=5.75 Hz, 2H), 2.24(s, 6H); MS (APCI) m/z 540 [M+H]⁺.

Example 101

4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide

Following the method described forN-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide,compound4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzene-sulfonamidewas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 51% yield and isolated as a white solid after lyophilization fromMeCN/H₂O. Selected data: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.8 (s, 1H),8.1 (s, 1H), 7.9-7.6 (m, 6H), 6.75 (1H), 6.5 (1H), 3.9-3.7 (m, 8H), 3.15(m, 2H), 2.2 (s, 6H); MS (APCI) m/z 544 [M+H]⁺.

Example 102

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide

Following the method described forN-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide,compoundN-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamidewas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 42% yield and isolated as a white solid after lyophilization fromMeCN/H₂O. Selected data: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.82 (s, 1H),7.90 (s, 2H), 7.33 (t, J=5.94 Hz, 1H), 6.74 (d, J=2.31 Hz, 1H), 6.52 (d,J=2.30 Hz, 1H), 3.92-3.81 (m, 8H), 3.41-3.34 (m, 2H), 2.97 (s, 3H), 2.32(s, 6H); MS (APCI) m/z 448 [M+H]⁺.

Example 103

2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyphenoxy)aceticacid

A mixture of NaOH (1.8 g, 0.045 mol) and 4-hydroxy-3-methoxylbenzalde(3.10 g, 0.0203 mol) in water (20 mL) was mixed with bromoacetic acid(2.82 g, 0.0203 mol) and heated to reflux for 6 h. The reaction mixturewas adjusted to pH 3.0 by adding a HCl solution. The solid was filteredoff and further washed with cold water and ethyl acetate (2×30 mL) toyield (4-formyl-2-methyl-phenoxy)-acetic acid (2.89 g, 67.7%).2-Amino-4,6-dimethoxy-benzamide (150 mg, 0.764 mmol) with(4-formyl-2-methyl-phenoxy)-acetic acid (160 mg, 0.764 mmol), sodiumhydrogen sulfite (150 mg, 58.5%) and p-toluenesulfonic acid monohydrate(15 mg) in N,N-dimethyl acetamide (10 mL) were heated to 150° C. for 16h. N,N-dimethyl acetamide was removed under vacuum and the residue waspoured into water (50 mL). The solid was filtered off and furtherpurified by base/acid extractions/washes to yield2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyphenoxy)aceticacid (25 mg, 8.1%). Selected data: MS (ES) m/z: 387.1; MP 275-277° C.

Example 104

5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one

A mixture of 2-amino-4,6-dimethoxy-benzamide (0.71 g, 3.71 mmol),3,5-dimethyl-4-benzyloxy benzaldehyde (0.94 g, 3.90 mmol), sodiumhydrogensulfite (0.68 g, 3.90 mmol) and p-toluenesulfonic acid (70 mg,0.37 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 150° C. for16 h. The reaction mixture was cooled to room temperature and dilutedwith water (200 mL). The resulting solid was collected by filtration andwashed with hexanes to afford2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one asa white solid (1.2 g, 79%).

A mixture of2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one(1.2 g, 2.92 mmol) and magnesium bromide (0.644 g, 3.5 mmol) in pyridine(50 mL) was stirred at reflux for 12 h. The mixture was concentrated andthe solid residue was made into slurry with HCl (2 N, 100 mL). The solidwas collected by filtration, washed with water and hexanes to yield2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-hydroxy-7-methoxy-3H-quinazolin-4-oneas a white solid (0.76 g, 65%). A solution of ammonium formate (0.945 g,15 mmol) and2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-hydroxy-7-methoxy-3H-quinazolin-4-one(0.1 g, 0.25 mmol) in DMF (50 mL) was mixed with palladium carbon (0.1g) and stirred at 85° C. for 14 h. The resulting suspension was cooledto room temperature, passed through a Celite pad, and washed with DCM.The filtrate was concentrated and the residue was diluted with water (20mL). The resulting solid was collected by filtration and washed withhexanes to afford5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one(57 mg, 74%) as light yellow solid. Selected data: MS (ES) m/z: 312.94;MP 291.3-293° C.

Example 105

2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethylpropylcarbamate

A mixture of the compound of Example 20 (0.070 g, 0.19 mmol), propylisocyanate (0.088 mL, 0.94 mmol), and TEA (0.14 g, 1.1 mmol) in THF (4.0mL) was stirred at 70° C. for 16 h. The mixture was filtered, washedwith THF, and the solvent was removed under reduced pressure. Theresidue was dissolved in EtOAc (50 mL) and washed with saturated aqueoussodium bicarbonate (50 mL), dried and the solvent was removed underreduced pressure. The resulting solid was chromatographed on silica gelto yield2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethylpropylcarbamate (0.035 g, 41%) as an off-white solid: Selected data: ¹HNMR (300 MHz, DMSO-d₆) δ 11.82 (s, 1H), 7.90 (s, 2H), 7.23 (t, J=5.27Hz, 1H), 6.74 (d, J=2.32 Hz, 1H), 6.52 (d, J=2.31 Hz, 1H), 4.27 (t,J=4.29 Hz, 2H), 3.99 (t, J=4.29 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H),3.02-2.86 (m, 2H), 2.29 (s, 6H), 1.50-1.30 (m, 2H), 0.84 (t, J=7.33 Hz,3H); MS (APCI) m/z 456 [M+H]⁺.

Example 106

2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethylmethylcarbamate

Following the method described for2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethylpropylcarbamate, compound2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethylmethylcarbamate was made from2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 11% yield and isolated as an off-white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 11.82 (s, 1H), 7.90 (s, 2H), 7.08 (m, 1H), 6.74 (d, J=2.29Hz, 1H), 6.52 (d, J=2.27 Hz, 1H), 4.27 (t, J=4.55 Hz, 2H), 3.99 (t,J=4.55 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.60 (d, J=4.57 Hz, 3H),2.29 (s, 6H); MS (APCI) m/z 428 [M+H]⁺.

Example 107

N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide

A mixture of compound2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.060 g, 0.16 mmol), p-toluoyl chloride (0.028 mL, 0.21 mmol), andPS-DIEA (0.057 g, 0.21 mmol) in CH₂Cl₂ (4.0 mL) was stirred at roomtemperature for 16 h. The mixture was filtered, washed with CH₂Cl₂ andthe solvent was removed under reduced pressure. The resulting residuewas chromatographed on silica gel to yieldN-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide(0.037 g, 51%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ11.80-11.00 (s, 1H), 8.69 (t, J=5.43 Hz, 1H), 7.88 (s, 2H), 7.79 (d,J=8.19 Hz, 2H), 7.28 (d, J=8.00 Hz, 2H), 6.73 (d, J=2.31 Hz, 1H), 6.51(d, J=2.31 Hz, 1H), 3.94 (t, J=5.59 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H),3.72-3.60 (m, 2H), 2.36 (s, 3H), 2.27 (s, 6H); MS (APCI) m/z 488 [M+H]⁺.

Example 108

2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethylcyclohexylcarbamate

A mixture of Example 18 (0.100 g, 0.270 mmol), cyclohexylisocyanate (172μL, 1.35 mmol), and Et₃N (263 μL, 1.89 mmol) in THF (1.00 mL) wasstirred at reflux for 4 h then diluted with EtOAc (200 mL) and washedwith saturated aqueous ammonium chloride (3×75 mL) and brine (75 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was chromatographed on silica gel(12 g, CH₂Cl₂/CH₃OH) and the product freeze dried from MeCN/H₂O toprovide2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethylcyclohexylcarbamate (0.0981 g, 73%) as a white solid. ¹H NMR (300 MHz,DMSO-d₆δ) 11.82 (s, 1H), 7.90 (s, 2H), 7.24-7.05 (m, 1H), 6.73 (d,J=2.30 Hz, 1H), 6.52 (d, J=2.31 Hz, 1H), 4.30-4.22 (m, 1H), 4.03-3.95(m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.29 (s, 6H), 1.82-1.46 (m, 5H),1.18 (m, 5H); MS (APCI) m/z 496 [M+H]⁺.

Example 109

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide

Following the methodology described for Example 100, the title compoundwas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 41% yield and isolated as an off-white solid: MS (APCI) m/z 510[M+H]⁺.

Example 110

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzenesulfonamide

Following the methodology described for Example 100, the title compoundwas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 50% yield and isolated as an off-white solid: MS (APCI) m/z 524[M+H]⁺.

Example 111

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide

Following the methodology described for Example 107, the title compoundwas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 46% yield and isolated as a white solid: MS (APCI) m/z 526 [M+Na]⁺.

Example 112

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide

Following the methodology described for Example 107, the title compoundwas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 40% yield and isolated as a white solid: MS (APCI) m/z 412 [M+H]⁺.

Example 113

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzamide

Following the methodology described for Example 107, the title compoundwas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 66% yield and isolated as a white solid: MS (APCI) m/z 474 [M+H]⁺.

Example 114

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide

Following the methodology described for Example 107, the title compoundwas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 59% yield and isolated as a white solid: MS (APCI) m/z 440 [M+H]⁺.

Example 115

1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-methylurea

A mixture of compound2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.10 g, 0.27 mmol), methylisocyanate (0.020 g, 0.35 mmol), and Et₃N(0.034 g, 0.35 mmol) in THF (4.0 mL) was stirred at room temperature for16 hours. The mixture was filtered, washed with CH₂Cl₂ and the solventwas removed under reduced pressure. The resulting residue waschromatographed on silica gel to yield the title compound (0.082 g, 71%)as a white solid: MS (APCI) m/z 449 [M+Na]⁺.

Example 116

1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-(4-methoxyphenyl)urea

Following the methodology described for Example 115, the title compoundwas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 57% yield and isolated as a white solid: MS (APCI) m/z 541 [M+Na]⁺.

Example 117

1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-phenylurea

Following the methodology described for Example 115, the title compoundwas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 59% yield and isolated as a light yellow solid: MS (APCI) m/z 489[M+H]⁺.

Example 118

3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1,1-dimethylurea

Following the methodology described for Example 115, the title compoundwas made from2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-onein 59% yield and isolated as a white solid: MS (APCI) m/z 441 [M+H]⁺.

Example 119 Quantification of ApoA-I mRNA

In this example, ApoA-I mRNA in tissue culture cells was quantitated tomeasure the transcriptional up-regulation of ApoA-I when treated with acompound of the invention.

HepG2 cells (˜2×10⁵ per well) were placed in a 24-well plate in ˜400 μLMEM, supplemented with 0.5% (v/v) FBS, 24 h before addition of thecompound of interest. At time of harvesting, the spent media was removedfrom the HepG2 cells and immediately placed on ice (for immediate use)or at −80° C. (for future use) in ApoA-I and albumin ELISAs. The cellsremaining in the plate wells were rinsed in 200 μL PBS. PBS wascarefully removed to avoid removing any loosely attached cells.

Once the PBS was removed, 85 μL cell lysis solution was added the cellsin each well and incubated for 5-10 min at room temperature, to allowfor complete cell lysis and detachment. mRNA was then prepared using the“mRNA Catcher PLUS plate” from Invitrogen, according to the protocolsupplied. After the last wash, as much wash buffer as possible wasaspirated without allowing the wells to dry. Elution Buffer (E3, 80 μL)was then added to each well. mRNA was then eluted by incubating the mRNACatcher PLUS plate with Elution Buffer for 5 min at 68° C. and thenimmediately placing the plate on ice.

The eluted mRNA isolated was then used in a one-step real-time roomtemperature-PCR reaction, using components of the Ultra Sense Kittogether with Applied Biosystems primer-probe mixes. Real-time PCR datawas analyzed, using the Ct values, to determine the fold induction ofeach unknown sample, relative to the control (that is, relative to thecontrol for each independent DMSO concentration).

An active compound is one that causes a >15% increase in ApoA-I mRNA ata concentration less than or equal to 100 uM.

Effect on Ex- ApoA-I am- mRNA ple # Compound Name levels 107N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 4-methylbenzamide106 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)-2,6-dimethyl-phenoxy)ethyl methylcarbamate 1052-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate 102N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide 1014-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)benzenesulfonamide100 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide 992-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 99 N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide 2-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Inactivedihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)isoindoline-1,3-dione98 2-(4-hydroxy-3-methylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 972-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 962-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 956-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)- Active3,5-dimethylphenyl)quinazolin-4(3H)-one 956-bromo-2-(4-(2-hydroxyethoxy)-3,5- Activedimethylphenyl)quinazolin-4(3H)-one 94 6-bromo-2-(4-hydroxy-3,5- Activedimethylphenyl)quinazolin-4(3H)-one 93(E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N- dimethylformimidamide92 2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin- Active 4(3H)-one5,7-dimethoxy-2-(3-nitrophenyl)quinazolin-4(3H)- Inactive one 912-(4-amino-3,5-dimethylphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one90 5,7-dimethoxy-2-(4-methoxy-3,5- Activedimethylphenyl)quinazolin-4(3H)-one 892-(2-chloro-6-methylpyridin-4-yl)-5,7- Activedimethoxyquinazolin-4(3H)-one 885,7-dimethoxy-2-(6-(4-(methylthio)phenyl)pyridin-2- Activeyl)quinazolin-4(3H)-one 875,7-dimethoxy-2-(6-methylpyridin-2-yl)quinazolin- Active 4(3H)-one 865,7-dimethoxy-2-(6-(4- Active(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin- 4(3H)-one 855,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one Active 842-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5- Activemethoxyquinazolin-4(3H)-one 832-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)- Active one 822-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6- Activemethoxyquinazolin-4(3H)-one4-(4-ethoxy-5,7-dimethoxyquinazolin-2-yl)-2,6- Inactive dimethylphenol81 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6- Active(morpholinomethyl)quinazolin-4(3H)-one 805,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5- Activedimethylphenyl)quinazolin-4(3H)-one 795,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5- Activedimethylphenyl)quinazolin-4(3H)-one 782-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7- Activedimethoxypyrido[2,3-d]pyrimidin-4(3H)-one 772-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- Activedimethylquinazolin-4(3H)-one 76 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-Active dimethylphenoxy)ethanol 752-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 1045-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7- Activemethoxyquinazolin-4(3H)-one 747-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy- Active1,6-naphthyridin-5(6H)-one2-(4-(2-(benzyloxy)ethoxy)-3,5-dimethylphenyl)-5,7- Inactivedimethoxypyrido[2,3-d]pyrimidin-4(3H)-one 73N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4- Activeoxo-3,4-dihydroquinazolin-6-yl)acetamide 722-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)- Active5,7-dimethoxyquinazolin-4(3H)-one 712-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1- Activemethylquinazolin-4(1H)-one 702-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- Activedimethoxypyrido[2,3-d]pyrimidin-4(3H)-one 695,7-dimethoxy-2-(4-methoxy-3- Active(morpholinomethyl)phenyl)quinazolin-4(3H)-one 682-(4-hydroxy-3,5-dimethylphenyl)-5,7- Activedimethoxypyrido[2,3-d]pyrimidin-4(3H)-one 672-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 66 5,7-dimethoxy-2-(4- Active(morpholinomethyl)phenyl)quinazolin-4(3H)-one 65N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)phenyl)-2-hydroxyacetamide 642-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)-2,6-dimethylphenoxy)acetic acid 632,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)- Active1,6-naphthyridin-5(6H)-one 62 2-(4-hydroxy-3,5-dimethylphenyl)-6- Active(morpholinomethyl)quinazolin-4(3H)-one 617-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4- Activedimethoxy-1,6-naphthyridin-5(6H)-one 60N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)-2,6-dimethylphenyl)-2-hydroxyacetamide 595,7-dimethoxy-2-(4-((4-methylpiperazin-1- Activeyl)methyl)phenyl)quinazolin-4(3H)-one 582-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7- Activedimethoxyquinazolin-4(3H)-one 1032-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)-2-methoxyphenoxy)acetic acid 572-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 562-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 552-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)-2,6-dimethylphenoxy)acetamide 54N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4- Activedihydroquinazolin-6-yl)acetamide 533-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)phenyl)propanoic acid 2-(2-(4-chlorophenoxy)pyridin-3-yl)-5,7-Inactive dimethoxyquinazolin-4(3H)-one 513-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7- Active(morpholinomethyl)isoquinolin-1(2H)-one 507-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4- Activedimethoxy-1,6-naphthyridin-5(6H)-one 495,7-dimethoxy-2-(4-morpholinophenyl)quinazolin- Active 4(3H)-one 482-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7- Activedimethoxyquinazolin-4(3H)-one 472-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7- Activedimethoxyquinazolin-4(3H)-one 462-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 452-(4-(bis(2-hydroxyethyl)amino)phenyl)quinazolin- Active 4(3H)-one 442-(4-(dimethylamino)pyridin-1-yl)-6,7- Activedimethoxyquinazolin-4(3H)-one 435,7-dimethoxy-2-(4-(4-methylpiperazin-1- Activeyl)phenyl)quinazolin-4(3H)-one 422-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7- Activedimethoxyquinazolin-4(3H)-one 41 2-(4-(4-oxo-3,4-dihydroquinazolin-2-Active yl)phenoxy)acetamide 402-(4-(dimethylamino)naphthalene-1-yl)quinazolin- Active 4(3H)-one 392-(4-(4-oxo-3,4-dihydroquinazolin-2- Active yl)phenoxy)acetic acid 382-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)phenoxy)acetamide 37 2-(4-(dimethylamino)naphthalene-1-yl)-5,7-Active dimethoxyquinazolin-4(3H)-one 362-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin- Active 4(3H)-one 352-(4-(2-hydroxyethoxy)-3,5- Active dimethylphenyl)quinazolin-4(3H)-one34 2-(3,5-dimethyl-4-(2- Activemorpholinoethoxy)phenyl)quinazolin-4(3H)-one 335,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one Active 322-(3-chloro-4-hydroxyphenyl)-5,7- Active dimethoxyquinazolin-4(3H)-one31 2-(4-hydroxy-3-methoxyphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 305,7-dimethoxy-2-(4-methoxyphenyl)quinazolin- Active 4(3H)-one 292-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin- Active 4(3H)-one 282-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 265,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one Active 242-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin- Active 4(3H)-one 233-(3,5-dimethyl-4-(2-(4-methylpiperazin-1- Activeyl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)- one 224-(2-(4-(6,8-dimethoxyisoquinolin-3-yl)-2,6- Activedimethylphenoxy)ethyl)morpholine 212-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one5,7-dimethoxy-2-p-tolylquinazolin-4(3H)-one Inactive 202-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 193-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8- Activedimethoxyisoquinolin-1(2H)-one 18 4-(6,8-dimethoxyisoquinolin-3-yl)-2,6-Active dimethylphenol 173-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2- Activemethyl-7-(morpholinomethyl) isoquinolin-1(2H)-one 173-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy- Active2,7-dimethylisoquinolin-1(2H)-one 167-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy- Active1,6-naphthyridin-5(6H)-one 156,8-dimethoxy-3-(4-hydroxy-3,5-dimethylphenyl)- Active2H-1,2-benzothiazine-1,1-dioxide 143-(4-(2-hydroxy-2-methylpropoxy)-3,5- Activedimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)- one 132-(4-hydroxy-3,5-dimethylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one 122-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4- Activemethoxy-1,6-naphthyridin-5(6H)-one 113-(4-hydroxy-3,5-dimethylphenyl)-7- Active(morpholinomethyl)isoquinolin-1(2H)-one 103-(4-(2-(dimethylamino)ethoxy)-3,5- Activedimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)- one 93-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8- Activedimethoxyisoquinolin-1(2H)-one 87-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin- Active 5(6H)-one 73-(4-hydroxy-3,5-dimethylphenyl)-6,8- Activedimethoxyisoquinolin-1(2H)-one 73-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2- Activemethylisoquinolin-1(2H)-one 63-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin- Active 1(2H)-one3-(3-fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin- Inactive 1(2H)-one 54-(1,6-naphthyridin-7-yl)phenol Active 44-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2- Activeamino-5-guanidinopentanoate 3 4-(Isoquinolin-3-yl)phenyl 2-amino-5-Active guanidinopentanoate tetrahydrochloride 24-Isoquinolin-3-yl-phenol Active 13-(4-Hydroxyphenyl)-2H-isoquinolin-1-one Active 1082-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)-2,6-dimethylphenoxy)ethyl cyclohexylcarbamate 109N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide 110N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzenesulfonamide 111 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 4-methoxybenzamide112 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)acetamide 113N-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Active dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzamide 114 N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-Active dihydroquinazolin-2-yl)-2,6- dimethylphenoxy)ethyl)isobutyramide115 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 3-methylurea 1161-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-(4-methoxyphenyl)urea 117 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 3-phenylurea 1183-(2-(4-(5,7-dimethoxy-4-oxo-3,4- Activedihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)- 1,1-dimethylurea

Example 120 ApoA-I mRNA and Protein Induction

In this example, ApoA-I mRNA and secreted protein from tissue culturecells were quantitated. The assay can be used to determine the potencyfor compounds of interest, including those of the present invention.

HepG2 cells or primary human hepatocytes (BD Gentest, lot 107) (˜2×10⁵per well) were placed in a 24-well plate in ˜400 μL MEM, supplementedwith 0.5% (v/v) FBS, 24 h before addition of the compound of interest.The compounds of interest were dissolved in DMSO at 0.05% (v/v).Appropriate volumes of the stock solutions of the compounds in DMSO werethen added to appropriate volumes of MEM, supplemented with 0.5% (v/v)FBS, to achieve the desired concentration (for example, 1 μL of acompound stock into 1 mL of MEM, supplemented with 0.5% (v/v) FBS).

Just prior to compound addition to the cells, the growth media wasaspirated and replaced with 300 μL of fresh MEM, supplemented with 0.5%(v/v) FBS, followed by addition of 300 μL of the compound of interest inMEM, supplemented with 0.5% (v/v) FBS, to achieve the desired finalcompound concentration in a total volume of 600 μL. The finalconcentration of diluent (DMSO) was 0.05% (v/v).

Cells were incubated for the desired time. The cell media was thenharvested, as were the cells. ApoA-I mRNA was measured as described inExample 119. Secreted ApoA-I was measured using an ApoA-I ELISA, asdescribed below:

ApoA-I ELISA

In this example, the ApoA-I secreted into the media from tissue culturecells was quantitated to assess induction of endogenous ApoA-I proteinsecretion from cells treated with various small molecule compounds, suchas those of the present invention.

At time of harvesting, spent media from the HepG2 cell cultures orprimary cell culture was removed and stored at −80° C. in 1.5 mLmicrofuge tubes.

For the human ApoA-I ELISA, an ELISA plate was coated with ˜100 μL/wellhuman ApoA-I capture antibody diluted to ˜2 μg/mL in coating buffer for˜1 h at room temperature. The plate was then washed three times in washbuffer. The plate was then blocked with ˜200 μL/well human ApoA-Iblocking buffer for at least ˜30 min at room temperature.

Samples for use in generating a standard curve were prepared from spentmedia (MEM, supplemented with 0.5% (v/v) FBS) from HepG2 or primarycells treated with DMSO for 48 h. Serial 2 fold dilutions of the mediawere prepared in MEM, supplemented with 0.5% (v/v) FBS. The unknownsamples—from the cultures treated with the compounds of interest—werealso diluted in MEM, supplemented with 0.5% (v/v) FBS. The plate waswashed three times in wash buffer. The standard curve and unknownsamples (100 μL/well), in triplicate, were added to the plate and it wasincubated for 1.5 h at room temperature.

The plate was washed three times in wash buffer. Human ApoA-I detectionantibody, diluted 1:1000 in PBS, was added (100 μL/well) and the platewas incubated for 1 h at room temperature. The plate was washed threetimes in wash buffer.

Goat anti-rabbit IgG H & L chain specific peroxidase conjugate, diluted1:2000 in PBS, was added (100 μL/well) and the plate was incubated for40 min at room temperature in the dark. The plate was washed six timesin wash buffer.

TMB liquid substrate was added (100 μL/well) and the plate was incubatedon a shaker underneath tin foil during development. Once a sufficient“blue” color had been achieved, stop solution (50 μL/well, 1 M H₂SO₄)was added and mixed thoroughly on the plate shaker. Air bubbles wereremoved and the absorbance at 450 nm was determined, using a MolecularDevices SpectraMax 190 Plate Reader and the human ApoA-I ELISA Softmaxsoftware.

Experiment A

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-oneat 0, 2.5, 5, 10, 20, 40, 60, 80 and 100 μM in HepG2 cell culture (48 h)and assayed for ApoA-I mRNA and secreted protein (FIG. 1).

Experiment B

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-oneat 0, 2.5, 5, 10, 20, 40, 60, 80 and 100 μM in primary human hepatocytes(48 h) and assayed for ApoA-I mRNA and secreted protein (FIG. 2).

Example 121 In Vivo Efficacy

To test whether the efficacy of compounds of the invention observed invitro extended to an in vivo model, transgenic mice carrying multiplecopies of the human ApoA-I gene (Bisaha et al. (1995) J. Biol. Chem. 34,19979-88) or wild-type mice (C57BL/6 (Stock Number 000664) JacksonLaboratory (Bar Harbor, Me.)) were exposed to compounds of theinvention. In the transgenic mice, the exogenous human ApoA-I gene inthese mice enables them to express the human ApoA-I protein under thecontrol of its own promoter.

Seven to eight week old male mice were housed five per cage (10″×20″×8″with aspen chip bedding) with pelleted Rodent chow [Purina 5001] andwater available at all times. After an acclimation period of 1 week,animals were individually identified by numbering on tail and weighed.Mice were pre bled via the retro-orbital plexus, and 100 μL of blood wascollected in 1.5 mL Eppendorf tube containing 5 μL of 0.5 mM EDTA andchilled on ice. Plasma was collected after centrifuging the whole bloodat 14000 rpm [TOMY high speed micro-refrigerated centrifuge NTX-150] for10 min at 4° C. and frozen at −80° C. Mice were grouped based on havingan average body weight of 25 g.

A day following pre-bleed, mice were dosed by oral gavage or i.p. dailyusing a 20 gauge, 11/2″ curved disposable feeding needle (Popper &Sons); when B.I.D., mice were gavaged morning and afternoon (8 am and 5μm); when Q.D. mice were gavaged in morning (8 am). Compounds wereprepared each day in vehicle. One day prior to necropsy mice wereweighed and fasted overnight. On final day of dosing, mice weresacrificed post 2 h of dosing by inhalation of CO₂ and blood wasobtained via cardiac puncture (0.7-1.0 mL). Plasma was collected andfrozen at −80° C. Samples were assayed for ApoA-I by ELISA, and HDL-C byHPLC (Polaris 200 with an auto sampler Prostar 410 from Varian on aSuperose 6 10/30 column from Amersham). During necropsy, liver andenterocytes from the duodenum and jejunum of the small intestine werecollected, cleaned with cold PBS and frozen at −80° C. for furtheranalysis of compound and mRNA levels by Q-PCR.

Experiment A

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(10, 30 and 60 mg/kg of body weight, mpk) were BID administered tohApoA-I transgenic mice daily for seven days by oral gavage in 1% DMSO,2.5% Tween-80, 10% PEG-300 QS to water. Plasma was assayed for ApoA-I(FIG. 3), and HDL cholesterol (FIG. 4).

Experiment B

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(10, 30 and 60 mg/kg of body weight) were BID administered to wild typeC57BL/6 mice daily for three days by intraperitoneal administration in1% DMSO, 2.5% Tween-80, 10% PEG-300 QS to water. Plasma was assayed forApoA-I (FIG. 5), and HDL cholesterol (FIG. 6).

Experiment C

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(30 mg/kg of body weight) were BID administered to hApoA-I transgenicmice daily for seven days by oral gavage in 1% DMSO, 2.5% Tween-80, 10%PEG-300 QS to water. Plasma was assayed for ApoA-I and tissues wereassayed for mRNA (FIG. 7).

These results indicate that the compounds of the invention are usefulfor increasing the transcription of ApoA-I in vivo, and elevating plasmalevels of ApoA-I and circulating levels of HDL-C in wild type andhApoA-I transgenic mice. These results demonstrate that compounds of theinvention activate the human ApoA-I transgene in mice, leading to anincrease in circulating ApoA-I.

All references referred to herein are incorporated by reference in theirentirety. Other embodiments of the invention will be apparent to thoseskilled in the art from consideration of the specification and practiceof the invention disclosed herein. It is intended that the specificationand examples be considered as exemplary only, with a true scope andspirit of the invention being indicated by the following claims.

1-75. (canceled)
 76. A method of treating or reducing the risk ofacquiring a cardiovascular-, cholesterol-, or lipid-related disorder ina mammal suffering from or at risk of acquiring such disorder comprisingadministering a therapeutically effective amount of a compound viasurgical device or implant, wherein the compound is selected fromcompounds of Formula II:

and pharmaceutically acceptable salts thereof, wherein: X is N; Y is CO;R₁ and R₃ are each independently selected from alkoxy, alkyl, amino,halogen, and hydrogen; R₂ is selected from alkoxy, alkyl, alkenyl,alkynyl, amide, amino, halogen, and hydrogen; R₆ and R₈ are eachindependently selected from alkyl, alkoxy, amino, halogen, and hydrogen;R₅ and R₉ are each hydrogen; R₇ is selected from amino, amide, alkyl,hydroxyl, and alkoxy; R₁₀ is hydrogen; each W is independently selectedfrom C and N, wherein if W is N, then p is 0 or 1, and if W is C, then pis 1; for W—(R₁₀)_(p), W is N and p is 1; for W—(R₇)_(p), W is C and pis 1; for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is 0;Z₁ is a double bond, and Z₂ and Z₃ are each a single bond; with theproviso that if R₁ is hydrogen, then R₃ is alkoxy; with the proviso thatif R₃ is hydrogen, then R₁ is selected from amino and alkoxy; with theproviso that if R₇ is selected from alkyl, hydroxyl, and alkoxy, then atleast one of R₆ and R₈ is independently selected from alkyl, alkoxy,amino, and halogen.
 77. The method according to claim 76, wherein R₇ isamino.
 78. The method according to claim 77, wherein the compound ofFormula II is2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneor a pharmaceutically acceptable salt thereof.
 79. The method accordingto claim 76, wherein R₇ is selected from hydroxyl and alkoxy.
 80. Themethod according to claim 79, wherein the compound of Formula II isselected from:N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide;2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;and pharmaceutically acceptable salts thereof.
 81. The method accordingto claim 79, wherein R₆ and R₈ are each independently alkyl; R₂ ishydrogen; and R₇ is selected from hydroxyl and alkoxy substituted with ahydroxyl.
 82. The method according to claim 81, wherein the compound ofFormula II is2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-oneor a pharmaceutically acceptable salt thereof.
 83. The method accordingto claim 76, wherein R₇ is an amino or an alkoxy selected from the grouprepresented by Formula III:

wherein: A is selected from O and N; n is selected from 0, 1, 2, 3, 4and 5; B is selected from —C(O)N(R_(h))₂—, —S(O)₂N(R_(h))₂—, —C(O)—,—S(O)₂—, —C(O)O—, wherein each R_(h) is selected from alkyl, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl,heterocyclyl, and hydrogen; and R₂₀, if present, is selected from(C₁-C₆) alkyl, (C₁-C₆) alkenyl, (C₁-C₆) alkynyl, aryl, arylalkyl,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
 84. Themethod according to claim 83, wherein the compound of Formula II isselected from:2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethylcyclohexylcarbamate;N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide;N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide;1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-phenylurea;3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1,1-dimethylurea;and pharmaceutically acceptable salts thereof.
 85. The method accordingto claim 76, wherein the compound of Formula II is selected from:2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide;2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide;2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)aceticacid;N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide;2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;5,7-dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-pyrido[2,3-d]pyrimidin-4(3H)one;5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one;(E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide;2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyphenoxy)aceticacid;2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethylpropylcarbamate;2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethylmethylcarbamate;N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide;N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide;N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzenesulfonamide;N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide;N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzamide;1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-methylurea;1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-3-(4-methoxyphenyl)urea;and pharmaceutically acceptable salts thereof.
 86. A method of treatingor reducing the risk of acquiring a cardiovascular-, cholesterol-, orlipid-related disorder in a mammal suffering from or at risk ofacquiring such disorder comprising administering a therapeuticallyeffective amount of a compound via surgical device or implant, whereinthe compound is selected from:2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one;2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid;2-(4-(dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one;2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide;2-(4-(bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one;2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one;5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;5,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one;2-(4-(dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(dimethylamino)pyridin-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one;2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazol-4(1H)-one;2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;and5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one,and pharmaceutically acceptable salts thereof.
 87. A method of treatingor reducing the risk of acquiring a cardiovascular-, cholesterol-, orlipid-related disorder in a mammal suffering from or at risk ofacquiring such disorder comprising administering a therapeuticallyeffective amount of a compound via surgical device or implant, whereinthe compound is selected from compounds of Formula II:

and pharmaceutically acceptable salts thereof, wherein: X is N; Y is CO;R₁ and R₃ are each independently selected from alkoxy and hydrogen; R₂is selected from alkoxy, alkyl, and hydrogen; R₆ and R₈ are eachindependently selected from alkyl, alkoxy, chloride, and hydrogen; R₅and R₉ are each hydrogen; R₇ is selected from amino, hydroxyl, alkoxy,and alkyl substituted with a heterocyclyl; R₁₀ is hydrogen; or twoadjacent substituents selected from R₆, R₇, and R₈ are connected to forma heterocyclyl; each W is independently selected from C and N, whereinif W is N, then p is 0 or 1, and if W is C, then p is 1; forW—(R₁₀)_(p), W is N and p is 1; for W—(R₄)_(p), W is C, p is 1 and R₄ isH, or W is N and p is 0; Z₁ is a double bond, and Z₂ and Z₃ are each asingle bond; with the proviso that if R₂ is alkoxy or hydrogen, thenleast one of R₁ and R₃ is alkoxy; with the proviso that if R₇ isselected from hydroxyl and alkoxy, then at least one of R₆ and R₈ areindependently selected from alkyl, alkoxy, and chloride; with theproviso that if for W—(R₇)_(p), W is N and p is 0, then at least one ofR₆ and R₈ is selected from alkyl, alkoxy, and chloride.
 88. The methodaccording to claim 87, wherein the compound of Formula II is selectedfrom:3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one);2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one;2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one;2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide;2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide;and pharmaceutically acceptable salts thereof.
 89. The method accordingto claim 87, wherein R₇ is selected from an amino or an alkoxy selectedfrom the group represented by Formula III:

wherein: A is selected from O and N; n is selected from 0, 1, 2, 3, 4and 5; B is selected from —C(O)N(R_(h))₂—, —S(O)₂N(R_(h))₂—, —C(O)—,—S(O)₂—, and —C(O)O—, wherein each R_(h) is independently selected fromalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, and hydrogen; and R₂₀, if present, is selectedfrom (C₁-C₆) alkyl, (C₁-C₆) alkenyl, (C₁-C₆) alkynyl, aryl, arylalkyl,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
 90. Themethod of claim 89, wherein the compound of Formula II is selected from:N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide;2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide;and pharmaceutically acceptable salts thereof.
 91. A method of treatingor reducing the risk of acquiring a cardiovascular-, cholesterol-, orlipid-related disorder in a mammal suffering from or at risk ofacquiring such disorder comprising administering a therapeuticallyeffective amount of a compound via surgical device or implant, whereinthe compound is selected from compounds of Formula II:

and pharmaceutically acceptable salts thereof, wherein: X is N; Y is CO;R₁ and R₃ are each independently selected from alkoxy, alkyl, amino,halogen, and hydrogen; R₂ is selected from —N—C(O)—R₁₈, —N—SO₂—R₁₈,—CH₂—C(R₁₈)₃, —CH₂—N(R₁₈)₂, and —CH₂—O—R₁₈, wherein each R₁₈ isindependently selected from alkoxy, alkyl, alkenyl, amide, amino, aryl,arylalkyl, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, andhydrogen; R₆ and R₈ are each independently selected from alkyl, alkoxy,amino, halogen, and hydrogen; R₅ and R₉ are each hydrogen; R₇ isselected from amino, amide, alkyl, hydroxyl, and alkoxy; R₁₀ ishydrogen; each W is independently selected from C and N, wherein if W isN, then p is 0 or 1, and if W is C, then p is 1; for W—(R₁₀)_(p), W is Nand p is 1; for W—(R₇)_(p), W is C and p is 1; for W—(R₄)_(p), W is C, pis 1 and R₄ is H, or W is N and p is 0; Z₁ is a double bond, and Z₂ andZ₃ are each a single bond; with the proviso that if R₇ is selected fromalkyl, hydroxyl, and alkoxy, then at least one of R₆ and R₈ isindependently selected from alkyl, alkoxy, amino, and halogen.
 92. Themethod according to claim 91, wherein the compound of Formula II isselected from:N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one;N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;and pharmaceutically acceptable salts thereof.
 93. The method accordingto claim 91, wherein R₆ and R₈ are each independently alkyl; and R₇ isselected from hydroxyl and alkoxy.
 94. The method according to claim 91,wherein R₇ is selected from an amino or an alkoxy selected from thegroup represented by Formula III:

wherein: A is selected from O and N; n is selected from 0, 1, 2, 3, 4and 5; B is selected from —C(O)N(R_(h))₂—, —S(O)₂N(R_(h))₂—, —C(O)—,—S(O)₂—, —C(O)O—, wherein each R_(h) is selected from alkyl, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl,heterocyclyl, and hydrogen; and R₂₀, if present, is selected from(C₁-C₆) alkyl, (C₁-C₆) alkenyl, (C₁-C₆) alkynyl, aryl, arylalkyl,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
 95. Themethod according to claim 91, wherein R₆ and R₈ are each independentlyalkyl.
 96. A method of treating or reducing the risk of acquiring acardiovascular-, cholesterol-, or lipid-related disorder in a mammalsuffering from or at risk of acquiring such disorder comprisingadministering a therapeutically effective amount of a compound viasurgical device or implant, wherein the compound is selected fromcompounds of Formula II:

and pharmaceutically acceptable salts thereof, wherein: X is N; Y is CO;R₁ is selected from alkoxy or amino; R₃ is alkoxy; R₂ is selected fromalkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen; R₆and R₈ are each independently selected from alkyl, alkoxy, amino,halogen, and hydrogen; R₅ and R₉ are each hydrogen; R₇ is selected fromamino, amide, alkyl, hydroxyl, and alkoxy; R₁₀ is hydrogen; each W isindependently selected from C and N, wherein if W is N, then p is 0 or1, and if W is C, then p is 1; for W—(R₁₀)_(p), W is N and p is 1; forW—(R₇)_(p), W is C and p is 1; for W—(R₄)_(p), W is C, p is 1 and R₄ isH, or W is N and p is 0; Z₁ is a double bond, and Z₂ and Z₃ are each asingle bond.
 97. The method according to claim 96, wherein R₇ isselected from hydroxyl and alkoxy.
 98. The method according to claim 97,wherein the compound of Formula II is selected from:2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)aceticacid; 5,7-dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one;2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide;and pharmaceutically acceptable salts thereof.
 99. The method accordingto claim 96, wherein R₇ is selected from amide and amino.
 100. Themethod according to claim 99, wherein the compound of Formula II isselected from:5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one;N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide;2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxy-pyrido[2,3-d]pyrimidin-4(3H)one;and pharmaceutically acceptable salts thereof.
 101. The method accordingto claim 96, wherein R₇ is alkyl.
 102. The method according to claim101, wherein the compound of Formula II is selected from:3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoicacid;5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;and pharmaceutically acceptable salts thereof.
 103. The method accordingto claim 96, wherein R₆ and R₈ are each independently alkyl.
 104. Themethod according to claim 96, wherein R₇ is selected from an amino or analkoxy selected from the group represented by Formula III:

wherein: A is selected from O and N; n is selected from 0, 1, 2, 3, 4and 5; B is selected from —C(O)N(R_(h))₂—, —S(O)₂N(R_(h))₂—, —C(O)—,—S(O)₂—, —C(O)O—, wherein each R_(h) is selected from alkyl, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl,heterocyclyl, and hydrogen; and R₂₀, if present, is selected from(C₁-C₆) alkyl, (C₁-C₆) alkenyl, (C₁-C₆) alkynyl, aryl, arylalkyl,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
 105. Themethod according to claim 104, wherein R₆ and R₈ are each independentlyalkyl.
 106. The method of claim 76, wherein the cardiovascular-,cholesterol-, or lipid-related disorder is selected from acute coronarysyndrome, angina, arteriosclerosis, atherosclerosis, carotidatherosclerosis, cerebrovascular disease, cerebral infarction,congestive heart failure, congenital heart disease, coronary heartdisease, coronary artery disease, coronary plaque stabilization,dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familialhypercholeasterolemia, familial combined hyperlipidemia,hypoalphalipoproteinemia, hypertriglyceridemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, cardiac ischemia, metabolicsyndrome, multi-infarct dementia, myocardial infarction, obesity,peripheral vascular disease, reperfusion injury, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, lipoprotein abnormalitiesassociated with Alzheimer's disease, diabetes mellitus, syndrome X,impotence, multiple sclerosis, and Parkinson's disease.
 107. The methodof claim 87, wherein the cardiovascular-, cholesterol-, or lipid-relateddisorder is selected from acute coronary syndrome, angina,arteriosclerosis, atherosclerosis, carotid atherosclerosis,cerebrovascular disease, cerebral infarction, congestive heart failure,congenital heart disease, coronary heart disease, coronary arterydisease, coronary plaque stabilization, dyslipidemias,dyslipoproteinemias, endothelium dysfunctions, familialhypercholeasterolemia, familial combined hyperlipidemia,hypoalphalipoproteinemia, hypertriglyceridemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, cardiac ischemia, metabolicsyndrome, multi-infarct dementia, myocardial infarction, obesity,peripheral vascular disease, reperfusion injury, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, lipoprotein abnormalitiesassociated with Alzheimer's disease, diabetes mellitus, syndrome X,impotence, multiple sclerosis, and Parkinson's disease.
 108. The methodof claim 91, wherein the cardiovascular-, cholesterol-, or lipid-relateddisorder is selected from acute coronary syndrome, angina,arteriosclerosis, atherosclerosis, carotid atherosclerosis,cerebrovascular disease, cerebral infarction, congestive heart failure,congenital heart disease, coronary heart disease, coronary arterydisease, coronary plaque stabilization, dyslipidemias,dyslipoproteinemias, endothelium dysfunctions, familialhypercholeasterolemia, familial combined hyperlipidemia,hypoalphalipoproteinemia, hypertriglyceridemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, cardiac ischemia, metabolicsyndrome, multi-infarct dementia, myocardial infarction, obesity,peripheral vascular disease, reperfusion injury, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, lipoprotein abnormalitiesassociated with Alzheimer's disease, diabetes mellitus, syndrome X,impotence, multiple sclerosis, and Parkinson's disease.
 109. The methodof claim 96, wherein the cardiovascular-, cholesterol-, or lipid-relateddisorder is selected from acute coronary syndrome, angina,arteriosclerosis, atherosclerosis, carotid atherosclerosis,cerebrovascular disease, cerebral infarction, congestive heart failure,congenital heart disease, coronary heart disease, coronary arterydisease, coronary plaque stabilization, dyslipidemias,dyslipoproteinemias, endothelium dysfunctions, familialhypercholeasterolemia, familial combined hyperlipidemia,hypoalphalipoproteinemia, hypertriglyceridemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, cardiac ischemia, metabolicsyndrome, multi-infarct dementia, myocardial infarction, obesity,peripheral vascular disease, reperfusion injury, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, lipoprotein abnormalitiesassociated with Alzheimer's disease, diabetes mellitus, syndrome X,impotence, multiple sclerosis, and Parkinson's disease.
 110. The methodof claim 86, wherein the cardiovascular-, cholesterol-, or lipid-relateddisorder is selected from acute coronary syndrome, angina,arteriosclerosis, atherosclerosis, carotid atherosclerosis,cerebrovascular disease, cerebral infarction, congestive heart failure,congenital heart disease, coronary heart disease, coronary arterydisease, coronary plaque stabilization, dyslipidemias,dyslipoproteinemias, endothelium dysfunctions, familialhypercholeasterolemia, familial combined hyperlipidemia,hypoalphalipoproteinemia, hypertriglyceridemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, cardiac ischemia, metabolicsyndrome, multi-infarct dementia, myocardial infarction, obesity,peripheral vascular disease, reperfusion injury, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, lipoprotein abnormalitiesassociated with Alzheimer's disease, diabetes mellitus, syndrome X,impotence, multiple sclerosis, and Parkinson's disease.
 111. The methodaccording to claim 76, wherein the cardiovascular-, cholesterol-, orlipid-related disorder is selected from diabetes mellitus, myocardialinfarction, coronary artery disease, coronary heart disease, familialhypercholeasterolemia, acute coronary syndrome, angina, atherosclerosis,arteriosclerosis, renal artery atherosclerosis, peripheral vasculardisease, congestive heart failure, stroke, and Alzheimer's disease. 112.The method of claim 82, wherein the cardiovascular-, cholesterol-, orlipid-related disorder is diabetes mellitus.
 113. The method of claim82, wherein the cardiovascular-, cholesterol-, or lipid-related disorderis myocardial infarction.
 114. The method of claim 82, wherein thecardiovascular-, cholesterol-, or lipid-related disorder is coronaryartery disease.
 115. The method of claim 82, wherein thecardiovascular-, cholesterol-, or lipid-related disorder is coronaryheart disease.
 116. The method of claim 82, wherein the cardiovascular-,cholesterol-, or lipid-related disorder is familialhypercholeasterolemia.
 117. The method of claim 82, wherein thecardiovascular-, cholesterol-, or lipid-related disorder is acutecoronary syndrome.
 118. The method of claim 82, wherein thecardiovascular-, cholesterol-, or lipid-related disorder is angina. 119.The method of claim 82, wherein the cardiovascular-, cholesterol-, orlipid-related disorder is atherosclerosis.
 120. The method of claim 82,wherein the cardiovascular-, cholesterol-, or lipid-related disorder isarteriosclerosis.
 121. The method of claim 82, wherein thecardiovascular-, cholesterol-, or lipid-related disorder is renal arteryatherosclerosis.
 122. The method of claim 82, wherein thecardiovascular-, cholesterol-, or lipid-related disorder is peripheralvascular disease.
 123. The method of claim 82, wherein thecardiovascular-, cholesterol-, or lipid-related disorder is congestiveheart failure.
 124. The method of claim 82, wherein the cardiovascular-,cholesterol-, or lipid-related disorder is Alzheimer's disease.
 125. Amethod of increasing levels of high density lipoprotein cholesterol(HDL-C) in a mammal comprising administering a therapeutically effectiveamount of a compound via surgical device or implant, wherein thecompound is selected from compounds of Formula II:

and pharmaceutically acceptable salts thereof, wherein: X is N; Y is CO;R₁ and R₃ are each independently selected from alkoxy, alkyl, amino,halogen, and hydrogen; R₂ is selected from alkoxy, alkyl, alkenyl,alkynyl, amide, amino, halogen, and hydrogen; R₆ and R₈ are eachindependently selected from alkyl, alkoxy, amino, halogen, and hydrogen;R₅ and R₉ are each hydrogen; R₇ is selected from amino, amide, alkyl,hydroxyl, and alkoxy; R₁₀ is hydrogen; each W is independently selectedfrom C and N, wherein if W is N, then p is 0 or 1, and if W is C, then pis 1; for W—(R₁₀)_(p), W is N and p is 1; for W—(R₇)_(p), W is C and pis 1; for W—(R₄)_(p), W is C, p is 1 and R₄ is H, or W is N and p is 0;Z₁ is a double bond, and Z₂ and Z₃ are each a single bond; with theproviso that if R₁ is hydrogen, then R₃ is alkoxy; with the proviso thatif R₃ is hydrogen, then R₁ is selected from amino and alkoxy; with theproviso that if R₇ is selected from alkyl, hydroxyl, and alkoxy, then atleast one of R₆ and R₈ is independently selected from alkyl, alkoxy,amino, and halogen.
 126. The method of claim 76, wherein the surgicaldevice is a catheter.
 127. The method of claim 126, wherein the catheteris coated with the compound of Formula II or a pharmaceuticallyacceptable salt thereof.
 128. The method of claim 76, wherein theimplant is a stent.
 129. The method of claim 128, wherein the stent iscoated with the compound of Formula II or a pharmaceutically acceptablesalt thereof.
 130. The method of claim 86, wherein the surgical deviceis a catheter.
 131. The method of claim 130, wherein the catheter iscoated with the compound of Formula II or a pharmaceutically acceptablesalt thereof.
 132. The method of claim 86, wherein the implant is astent.
 133. The method of claim 132, wherein the stent is coated withthe compound of Formula II or a pharmaceutically acceptable saltthereof.
 134. The method of claim 87, wherein the surgical device is acatheter.
 135. The method of claim 134, wherein the catheter is coatedwith the compound of Formula II or a pharmaceutically acceptable saltthereof.
 136. The method of claim 87, wherein the implant is a stent.137. The method of claim 136, wherein the stent is coated with thecompound of Formula II or a pharmaceutically acceptable salt thereof.138. The method of claim 91, wherein the surgical device is a catheter.139. The method of claim 138, wherein the catheter is coated with thecompound of Formula II or a pharmaceutically acceptable salt thereof.140. The method of claim 91, wherein the implant is a stent.
 141. Themethod of claim 140, wherein the stent is coated with the compound ofFormula II or a pharmaceutically acceptable salt thereof.
 142. Themethod of claim 96, wherein the surgical device is a catheter.
 143. Themethod of claim 142, wherein the catheter is coated with the compound ofFormula II or a pharmaceutically acceptable salt thereof.
 144. Themethod of claim 96, wherein the implant is a stent.
 145. The method ofclaim 144, wherein the stent is coated with the compound of Formula IIor a pharmaceutically acceptable salt thereof.
 146. The method of claim125, wherein the surgical device is a catheter.
 147. The method of claim146, wherein the catheter is coated with the compound of Formula II or apharmaceutically acceptable salt thereof.
 148. The method of claim 125,wherein the implant is a stent.
 149. The method of claim 148, whereinthe stent is coated with the compound of Formula II or apharmaceutically acceptable salt thereof.
 150. The method of claim 82,wherein the surgical device is a catheter.
 151. The method of claim 150,wherein the catheter is coated with the compound of Formula II or apharmaceutically acceptable salt thereof.
 152. The method of claim 82,wherein the implant is a stent.
 153. The method of claim 152, whereinthe stent is coated with the compound of Formula II or apharmaceutically acceptable salt thereof.